Indole derivatives

ABSTRACT

Compounds represented by formula (I)  
                 
wherein all symbols represent the same meanings as described in specification. and salts thereof. Since the compound represented by the formula (I) binds and antagonizes to DP receptor, it is useful for the prevention or treatment against the disease such as allergic disorder, diseases accompanied with itching, secondary diseases generated by behaviors caused by itching, inflammation, chronic obstructive pulmonary disease, ischemic reperfusion disorder, pleuritis complicated by rheumatoid arthritis, cerebrovascular disease, and ulcerative colitis.

TECHNICAL FIELD

The present invention relates to indole derivatives.

More specifically, the present invention relates to indole derivativesrepresented by formula (I):

wherein all symbols have the same meanings as described below, thenon-toxic salts,(2) a process for the preparation of the same, and(3) a medicine comprising them as an active ingredient.

BACKGROUND ART

Prostaglandin D₂ (hereinafter referred to as “PGD₂”) are known as ametabolite in the arachidonic acid cascade, and are thought to be one ofchemical transmitters that take part in allergic disease, for example,allergic rhinitis, bronchial asthma, and conjunctivitis allergic. It hasbeen known that PGD₂ is produced from mast cells and free PGD₂ showsbronchoconstriction, permeability accentuation, vasodilation orshrinkage, mucus secretion promotion, and platelet aggregationinhibitory effect. It has been reported that PGD₂ induces airwaycontraction and rhinostenosis symptom in vivo and the increase in PGD₂concentration has been recognized in the pathologic topical of systemicmast cytosis (mastocytosis) patients, nasal allergy patients, bronchialasthma patients, atopic dermatitis patients, and urticaria patients, etc(New Eng. J. Med., 303, 1400-1404 (1980), Am. Rev. Respir. Dis., 128,597-602 (1983), J. Allergy Clin. Immunol., 88, 33-42 (1991), ArchOtolaryngol Head Neck Surg, 113, 179-83 (1987), J. Allergy Clin.Immunol., 82, 869-77 (1988), J. Immunol., 146, 671-6 (1991), J. AllergyClin. Immunol., 83, 905-12 (1989), N. Engl. J. Med., 315, 800-4 (1986),Am. Rev. Respir. Dis., 142, 126-32 (1990), J. Allergy Clin. Immunol.,87, 540-8 (1991), J. Allergy Clin. Immunol., 78, 458-61 (1986)). Also,PGD is considered to relate to neuro activities, especially, sleep,hormone secretion, and pain. Furthermore, there are reports suggestingparticipations in platelet aggregation, glycogen metabolism, oculartension adjustment and the like.

PGD₂ shows its effects by binding to DP receptor which is one ofreceptor thereof. A DP receptor antagonist binds and is antagonistic toits receptor so that it can inhibit the function. Accordingly, it isconsidered to be useful for the prevention and/or treatment of diseases,for example, allergic diseases (allergic rhinitis, allergicconjunctivitis, atopic dermatitis, bronchial asthma, food allergy,etc.), systemic mastocytosis, disorders due to systemic mastocyteactivation, anaphylactic shock, bronchoconstriction, urticaria, eczema,allergic bronchopulmonary aspergillosis, paranasal sinusitis, migraine,nasal polyp, hypersensitive angitis, eosinophilia, contact dermatitis,diseases accompanied with itching (such as atopic dermatitis, urticaria,allergic conjunctivitis, allergic rhinitis, contact dermatitis, etc.),secondary diseases (such as cataracta, retinodialysis, inflammation,infection, dysgryphia, etc.) generated by behaviors caused by itching(scratching behaviors, beating, etc.), inflammation, chronic obstructivepulmonary disease, ischemic reperfusion disorder, cerebrovasculardisorder, pleuritis complicated by rheumatoid arthritis, ulcerativecolitis and the like. Moreover, it is considered to relate to sleepingand platelet aggregation and to be useful for these diseases.

It is known that PGD₂ binds with chemoattractant receptor-homologousmolecule expressed on Th2 cells (CRTH2 besides DP receptor, and has themigration action on Th 2 cell, eosinophil, and basophil (J. Exp. Med.,193, 255-261 (2001), Blood, 98, 1942-1948 (2001)). Since PGD₂ is aligand to both of DP and CRTH2 receptors in vivo, DP receptorantagonists are expected to bind with CRTH2 receptor, and to antagonizethe biological activity.

So, it is considered to be useful for the prevention and/or treatment ofdiseases, allergic diseases, for example, allergic rhinitis, allergicconjunctivitis, atopic dermatitis, bronchial asthma, food allergy, etc.,systemic mastocytosis, disorders due to systemic mastocyte activation,anaphylactic shock, bronchoconstriction, urticaria, eczema, allergicbronchopulmonary aspergillosis, paranasal sinusitis, migraine, nasalpolyp, hypersensitive angitis, eosinophilia, contact dermatitis,diseases accompanied with itching such as atopic dermatitis, urticaria,allergic conjunctivitis, allergic rhinitis, contact dermatitis, etc.;secondary diseases such as cataracta, retinodialysis, inflammation,infection, dysgryphia, etc. generated by behaviors caused by itching(scratching behaviors, beating, etc.), inflammation, chronic obstructivepulmonary disease, ischemic reperfusion disorder, cerebrovasculardisorder, pleuritis complicated by rheumatoid arthritis, ulcerativecolitis and the like.

Some PGD₂ receptor antagonists are known conventionally, and BW-A868Crepresented by the following formula (A) is considered to be the mostselective:

Recently, PGD₂ receptor antagonists comprising thromboxane derivativeshave been published in WO 98/25915, WO 98/25919, WO 97/00853, WO98/15502 and the like.

As prostaglandin receptors, a lot of receptor including the subtypeexist and the pharmacological action is respectively different. Then, ifnew compounds that weakly bind to other prostaglandin receptors andspecifically bind to PGD₂ receptor, especially DP receptor can be found,there is a possibility to become a medicine having a little side effectbecause of disappear of other actions, and discovery of such a medicineis necessary.

DISCLOSURE OF THE INVENTION

The present inventors intensively studied to find a compound whichspecifically binds to PGD₂ receptor, especially DP receptor and show anantagonistic activity and found that the object could be attained byindole derivatives represented by formula (I), and thus the presentinvention has been completed.

That is, the present invention relates to indole derivatives representedby formula (I):

wherein R¹ represents (1) —COR⁶ or (2) —CH₂OR⁷,R⁶ represents (1) hydroxyl group, (2) C1-6 alkoxy group, (3) —NR⁸R⁹, (4)C1-6 alkoxy group substituted by phenyl group, or (5) C2-6 alkenyloxygroup,R⁷ represents (1) hydrogen atom or (2) C2-6 acyl group,R⁸ and R⁹ represent (1) hydrogen atom, (2) C1-6 alkyl group or (3)—SO₂R¹⁰, respectively,R¹⁰ represents (1) C1-6 alkyl group, (2) carbocyclic ring 1 (3) orheterocycle 1,D represents (1) a single bond, (2) C1-6 alkylene group, (3) C2-6alkenylene group, (4) —O—(C1-6 alkylene)- group,R² represents (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) halogenatom(s), (4) trihalomethyl group, (5) cyano group, or (6) hydroxylgroup,R³ and R⁴ represent (1) hydrogen atom, (2) C1-6 alkyl group, and (3)C1-6 alkoxy group, (4) C1-6 alkyl group substituted in C1-6 alkoxygroup, (5) halogen atom, (6) nitro group, (7) —NR¹¹R¹², (8)trihalomethyl group, (9) cyano group, (10) hydroxyl group, or (11)methoxy groups, respectively,R¹¹ and R¹² represent a hydrogen atom or C1-6 alkyl group, respectively,m represents 1 to 4,n represents 1 to 4,R⁵ represents

(2) C1-6 alkyl group substituted in C1-6 alkoxy group, or (3) C1-6alkoxy group substituted by C1-6 alkoxy group,G represents (1) a single bond, (2) C1-6 alkylene groupI (alkylene groupmay be substituted by hydroxyl group or C1-4 alkoxy group) that may bereplaced by 1 or 2 of oxygen atom(s) and/or sulfur atom(s), (3) C2-6alkenylene group (alkenylene group may be substituted by hydroxyl orC1-4 alkoxy group) that may be replaced by 1-2 of oxygen atom(s) andsulfur atom(s), (4) —CONR¹³—, (5) —NR¹⁴CO—, (6) —SO₂NR¹⁵—, (7)—NR¹⁶SO₂—, or (8) —N═N—,R¹³, R¹⁴, R¹⁵, and R¹⁶ represent hydrogen atom or C1-6 alkyl group,respectively,

represents (1) carbocyclic ring 2 (2) or heterocycle 2,carbocyclic ring 1 and carbocyclic ring 2 represent C3-15 monocycle,dicyclic or tricycle carbocyclic ring aryls that may be saturated all orpartially, respectively, heterocycle 1 and heterocycle 2 represent C3-15monocycle, dicyclic, or tricycle heterocyclic ring aryls that may besaturated all or partially, which contained 1-5 hetero atom(s) selectedfrom oxygen atom(s), nitrogen atom(s) or sulfur atom(s), respectively,carbocyclic ring 1, carbocyclic ring 2, heterocycle 1, and heterocycle 2may be substituted by 1-5 group(s) selected from (1) C1-6 alkyl group,(2) C1-10 alkoxy group, (3) C1-6 alkyl group substituted by C1-6 alkoxygroup, (4) halogen atom, (5) hydroxyl group, (6) trihalomethyl group,(7) nitro group, (8) —NR¹⁷R¹⁸, (9) phenyl group, (10) phenoxy group,(11) oxo group, (12) C2-6 acyl group, (13) cyano group, and (14)—SO₂R¹⁹, respectively,R¹⁷ and R¹⁸ represent hydrogen atom or C1-6 alkyl group, respectively,R¹⁹ represents C1-6 alkyl group, and

represents (1) a single bond or (2) a double bond,except for 2-(1-(4-benzyloxybenzoyl)-2-methyl-5-methoxyindol-3-yl)acetic acid methyl.) or non-toxic salts thereof,(2) the manufacturing methods, and(3) the medicines that contains them as active ingredients.

The C1-6 alkyl group in this specification includes methyl, ethyl,propyl, butyl, pentyl, hexyl group, and isomers thereof.

The C1-4 alkoxy group in this specification includes methoxy, ethoxy,propoxy, butoxy group, and isomers thereof.

The C1-6 alkoxy group in this specification includes methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy group, and isomers thereof.

The C1-10 alkoxy group in this specification includes methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy,decyloxy group, and isomers thereof.

The C2-6 alkenyloxy group in this specification includes ethenyloxy,propenyloxy, butenyloxy, pentenyloxy, hexenyloxy group and isomersthereof.

The C1-6 alkylene group in this specification includes methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylenegroup, and isomers thereof.

The C2-6 alkenylene group in this specification includes ethenylene,propenylene, butenylene, pentenylene, hexenylene group and isomersthereof.

The halogen atom in this specification includes fluorine, chlorine, thebromide, and iodine atom.

The trihalomethyl group in this specification means methyl groupsubstituted by three halogen atoms.

The trihalomethoxy group in this specification means methoxy groupsubstituted by three halogen atoms.

The C1-6 alkylene group that may be replaced by 1 to 2 oxygen atom(s)and/or sulfur atom(s) in this specification includes methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylenegroup, and group replaced 1 to 2 arbitrary carbon atoms of the abovealkylene by 1 to 2 oxygen atom(s) and/or sulfur atom(s).

The C2-6 alkenylene group that may be replaced by 1 to 2 oxygen atomand/or sulfur atoms in this specification includes ethenylene,propenylene, butenylene, pentenylene, hexenylene group, and groupreplaced 1 to 2 arbitrary carbon atom(s) of the above alkenylene by 1 to2 oxygen atom(s) and/or sulfur atom(s).

The C2-6 acyl group in this specification includes acetyl, propanoyl,butanoyl, pentanoyl, hexanoyl group, and isomers thereof.

In this specification, as 3 to 15-membered monocycle, dicycle ortricycle carbocyclic ring aryl that may be saturated all or partially,which are represented by carbocyclic ring 1 and carbocyclic rings, forexample, cyclopropane, cyclobutane, cyclopentane, cyelohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane,cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane,cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene,cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene,cyclooctadiene, benzene, pentalene, azulene, perhydroazulene,perhydropentalene, indene, perhydroindene, indane, naphthalene,tetrahydronaphthalene, perhydronaphthalene, heptalene, biphenylene,as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene,phenalene, phenanthrene, anthracene, spiro[4.4]nonane, spiro[4.5]decane,spiro[5.5]undecane, bicyclo[3.1.1]heptane, bicyclo[3.3.1]-2-heptene,bicyclo[2.2.2]octane, adamantane, and noradamantane ring, etc. areincluded.

In this specification, as 3 to 15-membered monocycle, dicycle ortricycle heterocyclic ring aryls that includes 1 to 5 hetero atomsselected from oxygen atom, nitrogen atom or sulfur atom, among 3 to15-membered monocycle, dicyclic ring or tricycle heterocycle aryls thatmay be saturated all or partally and includes 1 to 5 hetero atom(s)selected from oxygen atom, nitrogen atom or sulfur atom, which arerepresented by heterocycle 1 and heterocycle 2, pyrrole, imidazole,triazole, tetrazole, pyrazol, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiin,thiepin, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole,oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine,thiadiazine, thiazepine, thiadiazepin, indole, isoindole, indolizine,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene,dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine,purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline,cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene,benzoxepin, benzoxazepine, benzoxadiazepine, benzothiepine,benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine,benzofurazan, benzothiadiazole, benzotriazole, carbazole,beta-carboline, acridine, phenazine, dibenzofuran, xanthene,dibenzothiophene, phenothiazine, phenoxazine, phenoxathiine,thianthrene, phenanthridine, phenanthroline, perimidine ring, etc. areincluded.

As 3 to 15-membered monocycle, dicycle or tricycle heterocyclic ringaryls that may be saturated all or partially and includes 1 to 5 heteroatom(s) selected from oxygen atom, nitrogen atom or sulfur atom,aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazin, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, thiirane, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiin (dihydrothiopyran), tetrahydrothiin(tetrahydrothiopyran), dihydrothiepin, tetrahydrothiepin,perhydrothiepin, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydroxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepin,tetrahydrothiadiazepin, perhydrothiadiazepin, morpholine,thiomorpholine, oxathiane, indoline, isoindolin, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrodibenzothiophene, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzooxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzooxazepine, tetrahydrobenzooxazepine,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine,dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane,dioxaindan, benzodioxan, chroman, benzodithiolane, and benzodithianering, etc. are included.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkoxy and alkylene group includesstraight or branched ones. In addition, isomers on double bond, ring,fused ring (E-, Z-, cis-, trans-isomer), isomers generated fromasymmetric carbon atom(s) (R-, S-, α-, β-isomer, enantiomer,diastereomer), optically active isomers (D-, L-, d-, l-isomer), polarcompounds generated by chromatographic separation (more polar compound,less polar compound), equilibrium compounds, rotamer, mixtures thereofat voluntary ratios and racemic mixtures are also included in thepresent invention.

According to the present invention, unless otherwise indicated and as isapparent for those skilled in the art, symbol

indicates that it is bound to the opposite side of the sheet (namelyα-configuration), symbol

indicates that it is bound to the front side of the sheet (namelyβ-configuration), symbol

indicates that it is α-, β- or a mixture thereof, and symbol

indicates that it is a mixture of α-configuration and β-configuration.

PGD₂ receptor in this specification represents a receptor that PGD₂binds, not only the one found by present, but also the one that will befound in the future is included in the receptor. The desirable one is DPreceptor or CRTH2 receptor, and more desirably DP receptor.

The compounds in the present invention may be converted into thenon-toxic salt by a well-known method. The non-toxic salts are suitableto be allowed in pharmacology, and water-soluble.

Non-toxic salts include, for example, alkali metal salts (potassium,sodium, lithium, etc.), alkaline earth metal salts (calcium, magnesium,etc.), ammonium salts (tetramethylammonium, tetrabutylammonium, etc.),organic amine salts (triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine, N-methyl-D-glucamine, etc.), acid-addition salts(inorganic acid salts (hydrochloride, hydrobromate, hydroiodate,sulfate, phosphate, and nitrate, etc.), organic acid salts (acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,benzoate, citrate, methane sulfonate, ethane sulfonate, benzenesulfonate, toluene sulfonate, isethionate, glucuronate, gluconate,etc.), etc.

In non-toxic salts of compound in the present invention, solvatesthereof, or solvates of alkali (earth) metal salts, ammonium salts,organic amine salts, and acid-addition salts of the above compound inthe present invention, are included.

The solvates are preferably non-toxic and water-soluble. Appropriatesolvates, for example, solvates such as water, alcohol solvents(ethanol, etc.), etc. are included.

As R¹ in formula (I), —COR⁶ or —CH₂OR⁷ is suitable and COR⁶ is moresuitable.

As R⁶ in formula (I), a hydroxyl or C1-6 alkyl group is suitable.

As R⁷ in formula (I), a hydrogen atom or C2-6 acyl group is suitable anda hydrogen atom is more suitable.

As D in formula (I), a single bond or C1-6 alkyl group is suitable andC1-6 alkyl group is more suitable.

As R² in formula (I), C1-6 alkyl group is suitable and methyl group ismore suitable.

As R⁵ in formula (I),

is suitable.

As G in formula (I), C1-6 alkylene group that may be replaced by 1 to 2oxygen atom(s) and/or sulfur atom(s) is suitable and C1-6 alkylene groupthat may be replaced by an oxygen atom is more suitable.

As

in formula (I), heterocycle 2 is suitable and 3 to 10-membered monocycleor bicyclic heterocycle aryl that may be saturated all or partially andincludes 1 to 3 hetero atom(s) selected from oxygen atom, nitrogen atomor sulfur atom, is more suitable.

As

in formula (I), double bond is suitable.

In the compounds represented by formula (I), as suitable compounds, acompound represented by formula (I-A-1);

wherein R⁶⁻¹ in the formula represents hydroxyl or C1-6 alkoxy group,and other symbols represent the same meanings as described above, acompound represented by formula (I-A-2);

wherein all symbols represent the same meanings as described above, acompound represented by formula (I-A-3);

wherein all symbols represent the same meanings as described above, acompound represented by formula (I-A-4);

wherein all symbols represent the same meanings as described above, acompound represented by formula (I-A-5);

wherein all symbols represent the same meanings as described above, acompound represented by formula (I-A-6);

wherein all symbols represent the same meanings as described above, acompound represented by formula (I-A-7);

wherein R⁷⁻¹ in the formula represents C2-6 acyl group, and othersymbols represent the same meanings as described above, a compoundrepresented by formula (I-A-8);

wherein R⁶⁻² in the formula represents —NR⁸R⁹, and other symbolsrepresent the same meanings as described above are included.

In concrete compounds of the present invention, the compoundsrepresented in the following table 1 to 54, the compounds of examples,and non-toxic salts thereof are included.

In the tables, Me represents methyl group, and Et represents ethylgroup, and other symbols represent the same meanings as described above.TABLE 1 (I-A-1-1)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 2 (I-A-1-2)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 3 (I-A-2-1)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 4 (I-A-2-2)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 5 (I-A-3-1)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 6 (I-A-3-2)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 7 (I-A-4-1)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 8 (I-A-4-2)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

TABLE 9 (I-A-5-1)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 10 (I-A-5-2)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 11 (I-A-6-1)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 12 (I-A-6-2)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 13 (I-A-7-1)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 14 (I-A-7-2)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 15 (I-A-8-1)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 16 (I-A-8-2)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 17 (I-A-1-3)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 18 (I-A-1-4)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 19 (I-A-1-5)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 20 (I-A-1-6)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 21 (I-A-1-7)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 22 (I-A-1-8)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 23 (I-A-1-9)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 24 (I-A-1-10)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 25 (I-A-1-11)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 26 (I-A-1-12)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 27 (I-A-1-13)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 28 (I-A-1-14)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 29 (I-A-1-15)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 30 (I-A-1-16)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 31 (I-A-1-17)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 32 (I-A-1-18)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 33 (I-A-1-19)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 34 (I-A-1-20)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 35 (I-A-1-21)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 36 (I-A-1-22)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 37 (I-A-1-23)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 38 (I-A-1-24)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 39 (I-A-1-25)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 40 (I-A-1-26)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 41 (I-A-1-27)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 42 (I-A-1-28)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 43 (I-A-1-29)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 44 (I-A-1-30)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 45 (I-A-1-31)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 46 (I-A-1-32)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 47 (I-A-1-33)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 48 (I-A-1-34)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 49 (I-A-1-35)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 50 (I-A-1-36)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 51 (I-A-1-37)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 52 (I-A-1-38)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 53 (I-A-1-39)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 54 (I-A-1-40)

No. R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

Processes for the Preparation of the Compound in the Present Invention:

The compound of the present invention represented by formula (I) may beprepared by the following processes and the processes shown in examples.

a) Among the compounds represented by formula (I), the compound that R⁶represents —COR⁶ group and R¹ represents hydroxyl, that is, a compoundrepresented by formula (IA)

wherein all symbols have the same meanings as described above may beprepared by the following method.

The compound represented by formula (IA) may be prepared by subjectingthe compound represented by formula (II)

wherein R²⁰ in the formula represents allyl or benzyl group and R²⁻¹,R³⁻¹, R⁴⁻¹, and R⁵⁻¹ represent the same meaning as R², R³, R^(4,) andR⁵, and when protection of hydroxyl or amino group included in the grouprepresented by R²⁻¹, R³⁻¹, R⁴⁻¹, and R⁵⁻¹ is necessary, it is consideredto be protected. Other symbols represent the same meanings as describedabove to deprotection reaction of allyl group or benzyl group, and ifnecessary, deprotection reaction of protecting group.

A deprotection reaction of allylic ester, which is well known, may bereacted at temperature of 0-50° C., for example, in an organic solvent(dichloromethane, dimethyl formamide, tetrahydrofuran, dioxane, ethylacetate, and ethanol, etc.), under the absence or presence of a trapreagent (tributyltin hydroxide, dimedon, morpholine, pyrrolidine, and2-ethylhexanoic acid, etc.) and an organic acid (acetate, etc.), using ametal complex (tetrakis (triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II)dichloride, palladium acetate(II),and tris(triphenylphosphine)rhodium(I)chloride, etc.).

A deprotection reaction of benzyl ester, which is well known, may becarried out at temperature of 0-200° C., for example, in a solvent(ether (tetrahydrofuran, dioxane, dimethoxyethane, and diethyl ether,etc.), alcohol (methanol and ethanol, etc.), benzene (benzene andtoluene, etc.), ketones (acetone and methylethylketone, etc.), nitrile(acetonitrile etc.), amide (dimethylformamide etc.), water, ethylacetate, acetate, or two or more mixed solvent(s) thereof, etc.), underthe presence of a catalyst (palladium-carbon, palladium black, hydroxidepalladium, platinum oxide, and raney nickel, etc.), atmospheric orpressurized hydrogen atmosphere, or formate ammonium.

Deprotection reactions of protecting groups may be carried out by thefollowing methods.

The deprotection reactions of the protecting groups of hydroxyl or aminogroup are known well, for example,

(1) alkaline hydrolysis,

(2) a deprotection reaction under acid condition,

(3) a deprotection reaction by hydrolysis, and

(4) a deprotection reaction of silyl group, etc. are included.

These methods are concretely explained as follows,

(1) The deprotection reaction by alkaline hydrolysis may be carried outat temperature of 0-40° C., for example, in an organic solvent(methanol, tetrahydrofuran, dioxane or these mixed solvents, etc.),using an alkali metal (sodium hydroxide, potassium hydroxide, andlithium hydroxide, etc.), an alkaline earth metal (barium hydroxide andcalcium hydroxide, etc.), a carbonate (sodium carbonate and potassiumcarbonate, etc.), the solution, or these compounds.

(2) The deprotection reaction under acid condition may be carried out attemperature of 0-100° C., for example, under the presence or absence ofan organic solvent (methylene chloride, chloroform, dioxane, ethylacetate, anisole, methanol, ethanol, and isopropyl alcohol, etc.), or inthe solution, an organic acid (acetate, trifluoroacetic acid, andmethanesulfonic acid, etc.), an inorganic acid (hydrochloric acid andsulfate, etc.), or these compounds (hydrogen bromide/acetate etc.).

(3) The deprotection reaction by hydrolysis may be carried out at thetemperature of 0-200° C., for example, in a solvent (ethers(tetrahydrofuran, dioxane, dimethoxyethane, and diethyl ether, etc.),alcohol (methanol and ethanol, etc.), benzenes (benzene and toluene,etc.), ketone (acetone and methyl ethyl ketone, etc.), nitriles(acetonitrile etc.), amide (dimethyl formamide etc.), water, ethylacetate, acetate, or two or more mixed solvent(s) thereof, etc.), underthe presence of a catalyst (palladium-carbon, palladium black, hydroxidepalladium, platinum oxide, and raney nickel, etc.), atmospheric orpressurized hydrogen atmosphere, or formate ammonium.

(4) The deprotection reaction of silyl group may be carried out attemperature of 0-40° C., for example, in water and an organic solvent(tetrahydrofuran and acetonitrile, etc.) that can be mixed, usingtetrabutylammoniumfluoride.

As protecting groups of hydroxyl group, for example, methoxymethyl,2-tetrahydropyranyl, tert-butyl dimethylsilyl, tert-butyl diphenylsilyl, acetyl, benzyl, and 4-methoxybenzyl group, etc. are included.

As protecting groups of amino group. for example, benzyloxycarbonyl,t-butoxycarbonyl, trifluoroacetyl, and 9-fluorenylmethoxycarbonyl group,etc. are included.

They only have to be a group that can be left easily and selectivelyexcept the above as protecting groups of hydroxyl or amino group, andare not especially limited. For example, the group described in T. W.Greene, Protective Groups in Organic Synthesis 3rd edition, Wiley, NewYork, (1999) may be used.

Though the persons skilled in the art can understand easily, the aimedcompound of the present invention can be easily prepared by using thesedeprotection reactions properly.b) Among the compounds represented by formula (I), a compound wherein R¹represents —COR⁶ and R⁶ represents C1-6 alkoxy group, that is, thecompound represented by formula (IB)

wherein R⁶⁻³ represent C1-6 alkoxy group, and other symbols representthe same meaning as the described above may be prepared by the followingmethod.

The compound represented by formula (IB) may be prepared byesterification of the compound represented by formula (III)

wherein all symbols have the same meanings as the above and the compoundrepresented by formula (IV)R²¹—OH  (IV)wherein R²¹ represents C1-6 alkyl group, and then, if necessary by thedeprotection of the protecting group.

As esterification reactions that are well-known, for example,

(1) a method using acyl halide,

(2) a method using mixed acid anhydride, and

(3) a method using a condensing agent are included.

These methods are concretely explained as follows,

(1) The method using acyl halide may be carried out, for example, byreacting carboxylic acid with acyl halide (oxalyl chloride or thionylchloride, etc.) in an organic solvent (chloroform, methylene chloride,diethyl ether or tetrahydrofuran, etc.) or without a solvent at −20° C.to reflux temperature and then reacting the obtained acyl halide withalcohol in an inactive organic solvent (chloroform, methylene chloride,diethyl ether or tetrahydrofuran, etc.), under the presence of atertiary amine (pyridine, triethyl amine, dimethyl aniline,dimethylaminopyridine or diisopropylethylamine, etc.) at 0-40° C. Themethod may be carried out by reacting with acyl halide in an organicsolvent (dioxane, tetrahydrofuran) using an alkaline solution (sodiumbicarbonate, sodium hydroxide, etc.) at 0-40° C.

(2) The method using mixed acid anhydride may be carried out, forexample, by reacting carboxylic acid with acyl halide (epivaloylchloride, tosyl chloride, mesyl chloride, etc.), or an acid derivative(ethyl chloroformate or isobutyl chloroformate, etc.) in an organicsolvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran,etc.) or without a solvent, under the presence of a tertiary amine(pyridine, triethylamine, dimethylaniline, dimethylaminopyridine ordiisopropylethylamine, etc.) at 0-40° C. and then reacting the obtainedmixed acid anhydride with alchol in an organic solvent (chloroform,methylene chloride, diethyl ether or tetrahydrofuran, etc.) at 0-40° C.

(3) The method using a condensing agent may be carried out, for example,by reacting carboxylic acid with alchol in an organic solvent(chloroform, methylene chloride, dimethylformamide, diethyl ether ortetrahydrofuran, etc.), these mixed solvents, or without a solvent,under the presence or absence of a tertiary amine (pyridine,triethylamine, dimethylaniline or dimethylaminopyridine, etc.), using acondensing agent (1,3-dicyclohexyl carbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,methanesulphonyloxybenzotriazole, 3-methyl-2-fluoropyridinium tosilatemethyl or 1-propanephosphonic acid cyclic anhydride; PPA, etc.), with orwithout 1-hydroxybenzotiazole (HOBt), at 0-40° C.

It is suitable that the reaction described in (1), (2) and (3) may becarried out under an inert gas (argon and nitrogen, etc.) and water freecondition.

The deprotection reaction of the protecting group may be carried out bythe method similar to the above.c) Among the compounds represented by formula (I), a compound wherein R¹represents —COR⁶ and R⁶ represents —NR⁸R⁹, that is, the compoundrepresented by formula (IC)

wherein all symbols represent the same meaning as the above may beprepared by the following method.

The compound represented by formula (IC) may be prepared by amidationreaction of the compound represented by formula (III) and a compoundrepresented by formula (V)H—NR⁸⁻¹R⁹⁻¹  (V)wherein it is considered that hydroxyl or amino groups included in thegroup represented by R⁸⁻¹ and R⁹⁻¹ are optionally protected, andfurther, if necessary, by the deprotection of the protecting group.

As the amidation reactions that are well-known, for example,

(1) a method using acyl halide,

(2) a method using mixed acid anhydride, and

(3) a method using a condensing agent are included.

These methods are concretely explained as follows.

(1) The method using acyl halide may be carried out, for example, byreacting carboxylic acid with acyl halide (oxalyl chloride or thionylchloride, etc.) in an organic solvent (chloroform, methylene chloride,diethyl ether or tetrahydrofuran, etc.) or without a solvent at −20° C.to reflux temperature and then reacting the obtained acyl halide withamine in an inactive organic solvent (chloroform, methylene chloride,diethyl ether or tetrahydrofuran, etc.), under the presence of tertiaryamine (pyridine, triethyl amine, dimethyl aniline, dimethylaminopyridineor diisopropylethylamine, etc.) at 0-40° C. The method may be carriedout by reacting with the acyl halide in an organic solvent (dioxane,tetrahydrofuran) using an alkaline solution (sodium bicarbonate, sodiumhydroxide, etc.) at 0-40° C.

(2) The method using a mixed acid anhydride may be carried out, forexample, by reacting carboxylic acid with acyl halide (epivaloylchloride, tosyl chloride, mesyl chloride, etc.), or an acid derivative(ethyl chloroformate or isobutyl chloroformate, etc.) in an organicsolvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran,etc.) or without a solvent, under the presence of a tertiary amine(pyridine, triethylamine, dimethylaniline, dimethylaminopyridine ordiisopropylethylamine, etc.), at 0-40° C. and then reacting the obtainedmixed acid anhydride with amine in an organic solvent (chloroform,methylene chloride, diethyl ether or tetrahydrofuran, etc.) at 0-40° C.

(3) The method using a condensing agent may be carried out, for example,by reacting carboxylic acid with amine in an organic solvent(chloroform, methylene chloride, dimethylformamide, diethyl ether ortetrahydrofuran, etc.) or without a solvent, under the presence orabsence of a tertiary amine (pyridine, triethylamine, dimethylaniline ordimethylaminopyridine, etc.), using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide(EDC), 1,1′-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,methanesulphonyloxybenzotriazole, 3-methyl-2-fluoropyridinium tosilatemethyl or 1-propanephosphonic acid cyclic anhydride; PPA, etc.), with orwithout 1-hydroxybenzotiazole (HOBt), at 0-40° C.

It is suitable that the reaction described in (1), (2) and (3) may becarried out under an inert gas (argon and nitrogen, etc.) and water freecondition.

The deprotection reaction of the protecting group may be carried out bythe method similar to the above:d) Among the compounds represented by formula (I), a compound wherein R¹represents —CH₂OR⁷ and R⁷ represents a hydrogen atom, that is, acompound represented by formula (ID)

wherein all symbols represent the same meaning as the described abovemay be prepared by the following method.

The compound represented by formula (ID) may be prepared by reductivereaction of the compound represented by formula (III), and then, ifnecessary, by the deprotection of the protecting group.

The reductive reaction, which is well-known, may be carried out at 0-80°C., for example, in an organic solvent (tetrahydrofuran etc.) using anborane complex (borane-tetrahydrofuran complex, andborane-dimethylsulfide complex, etc.) or by reacting carboxylic acidwith the acid derivative chloro ethyl formate and chloro formateisobutyl, etc.) at 0-40° C. in an inert organic solvent (chloroform,methylene chloride, diethyl ether, and tetrahydrofuran, etc.) or withouta solvent under the presence of tertiary amine (pyridine, triethylamine,dimethyl aniline, and dimethylaminopyridine, etc.), and further,reacting the obtained mixed acid anhydride at 0-40° C. in an inertorganic solvent (chloroform, methylene chloride, diethyl ether, andtetrahydrofuran, etc.) using a reducing agent (sodium borohydride etc.).

The deprotection reaction of the protecting group may be carried out bythe method similar to the above.e) Among the compounds represented by formula (I), a compound wherein R¹represents —CH₂OR⁷ and R⁷ represents C2-6 acyl group, that is, acompound represented by formula (IE)

wherein R⁷⁻¹ represents C2-6 acyl group, other symbols represent thesame meaning as the described above may be prepared by the followingmethod.

The compound represented by formula (IE) may be prepared byesterification reaction of the compound represented by formula (VI)

wherein all symbols represent the same meaning as the described aboveand a compound represented by formula (VII)

wherein R²² represents C1-5 alkyl group and then, if necessary, by thedeprotection of the protecting group.

The esterification reaction and the deprotection reaction of theprotecting group may be carried out by the method similar to the above.f) among the compounds represented by formula (I), a compound wherein R¹represents —COR⁶ and R⁶ represents C1-6 alkoxy or C2-6 alkenyloxy group,that is, a compound represented by formula (IF)

wherein R⁶⁻⁴ represents C1-6 alkoxy group substituted by phenyl or C2-6alkenyloxy group, other symbols represent the same meaning as thedescribed above may be prepared by the following method.

The compound represented by formula (IF) may be prepared by amidationreaction of a compound represented by formula (VIII)

wherein all symbols represent the same meaning as the described aboveand a compound represented by formula (VII)

wherein R²² represents C1-5 alkyl group and then, if necessary, by thedeprotection of the protecting group.

The amidation reaction and the deprotection reaction of the protectinggroup may be carried out by the method similar to the above.

Among the compounds represented by formula (IF), a compound wherein R⁵represents

and G represents —O—(C1-5 alkylene)-, that is, a compound represented byformula (IF-1)

wherein G¹ represents —O—(C1-5 alkylene)-, other symbols represent thesame meaning as the described above may be prepared by theetherification reaction of a compound represented by formula (X)

wherein all symbols represent the same meaning as the described aboveand a compound represented by formula (XI)

wherein G2 represents C1-5 alkylene group, other symbols represent thesame meaning as the above and then, if necessary, by the deprotection ofthe protecting group.

This etherification reaction, which is well-known, may be carried out at0-60□ by reacting with the corresponding alcohol compound, for example,in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran,acetonitrile, benzene, and toluene, etc.) under the presence of an azocompound (diethyl azodicarboxylate (DEAD), azodicarboxylate diisopropyl,1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide),etc.), and phosphine compounds (triphenylphosphine, tributylphosphine,trimethylphosphine, and polymer support triphenylphosphine, etc.).

The deprotection reaction of the protecting group may be carried out bythe method similar to the above.

The compounds represented by formula (II), (IV), (V), (VII), (VII),(IX), (X), and (XI) are well-known or may be easily prepared by awell-known method.

For example, the compound represented by formula (II) may be prepared bythe method shown by the following reaction process 1 and 2.

For example, the compounds represented by formula (VIII) and (X) may beprepared by the method shown by the following reaction process 3 and 4.

D¹ represents a single bond or C1-6 alkylene group, D² represents C2-6alkenylene group, D³ represents C1-6 alkylene group, R²³ representshalogen atom or the hydroxyl, R²⁴ represents the protecting group ofhydroxyl, and other symbols represent the same meaning as the describedabove in the reaction process.

In the reaction process 1 to 4, the compounds represented by formula(XII), (XIII), (XVIII-1), (XIX), (XXII), (XXIII), (XVI), (XVII) and(XXX), which are used as starting materials, are well-known or may beeasily prepared by a well-known method.

For example, the compound represented by formula (XIV-1) may be preparedaccording to a method described in Tetrahedron., 30, 1445-1455 (1974).

The reaction product may be purified by usual purification methods, forexample, distillation and silicagel under normal or reduced pressure,high performance liquid chromatography, thin layer chromatography orcolumn chromatography that used magnesium trisilicate, or wash andrecrystallization, etc. The purification may be carried out at eachreaction or after some reactions.

Pharmacological Activities:

The compound of the present invention represented by formula (I)potently binds to a DP receptor and shows an antagonistic activity. Thiseffect was confirmed by the following receptor binding test usingprostanoid receptor-expressing cells.

(i) Receptor Binding Test Using Prostanoid DP Receptor-Expressing Cells

CHO cells expressing mouse DP receptors were prepared according to themethod of Hirata et al. (Proc. Natl. Acad. Sci., 91, 11192-11196 (1994))and used as a membrane standard.

A reaction solution (200 μL) containing the prepared membrane standard(30-166 μg) and ³H-PGD₂ was incubated at room temperature for 20minutes. The reaction was stopped with an ice-cold buffer (1 mL) and thebinding ³H-PGD₂ was trapped in on a glass filter by immediateaspiration-filtration under a reduced pressure, and its bindingradioactivity was measured using a liquid scintillation counter.

Kd value and Bmax value were obtained from Scatchard plots (Ann. N.Y.Acad. Sci., 51, 660 (1949)]. Non-specific binding was obtained as thebinding radioactivity in the presence of unlabeled PGD₂ at an excessamount (10 μmol/L). ³H-PGD₂ binding inhibition by the compound of thepresent invention was measured by adding ³H-PGD₂ (2.5 nmol/L) and thecompound of the present invention as various concentrations. Also, thefollowing buffers were used for the reactions.

Incubation Buffer:

HEPES-NaOH (25 mmol/L, pH 7.4)

EDTA (1 mmol/L)

MgCl₂ (5 mmol/L)

MnCl₂ (10 mmol/L)

Buffer for Washing:

Tris-HCl (10 mmol/L, pH 7.5)

NaCl (0.1 mol/L)

Bovine serum albumin (0.01%)

The dissociation constant (Ki) (μmol/L) of each compound was obtained bythe following equation.Ki=IC ₅₀/(1+([L]*/Kd))

[L*]: Concentration of radioligand

The result is shown in table 55. TABLE 55 Example No DP Ki (μM) 4 (4)0.0074

As shown in the above results, it is apparent that the compound of thepresent invention potently binds to DP receptor.

(ii) DP Antagonistic Activity Assay Using Prostanoid DPReceptor-Expressing Cells may be Examinated by the Following Method.

CHO cells expressing mouse DP receptor were prepared, inoculated onto a24-well microplate at 10⁵ cells/well, followed by culturing for 2 days,and used for the assay. Each well was washed with 500 μL of MEM (minimumessential medium), and 450 μL of assay medium (MEM containing 1 mmol/LIBMX, 2 μmol/L diclofenac and 0.1 or 1% BSA), followed by incubation at37° C. for 10 minutes. Then, an assay medium (50 μL) containing PGD₂alone or PGD₂ with a compound of the present invention was added theretoto start the reaction, and after the reaction at 37° C. for 10 minutes,500 μL of ice-cold trichloroacetatic acid (TCA) (10% w/v) was addedthereto to stop the reaction. The reaction solution was frozen once(−80° C.) and thawed, and cells were peeled using a scraper, followed bycentrifugation at 13,000 rpm for 3 minutes. The cAMP concentration wasmeasured with a cAMP assay kit using the resulting supernatant. That is,[¹²⁵I]-cAMP assay kit buffer was added to 125 μL of the supernatant togive a total amount of 500 μL, and the resulting mixture was mixed with1 mL of a chloroform solution of 0.5 mol/L tri-n-octylamine.Trichloroacetic acid (TCA) was extracted to the chloroform layer andremoved, the cAMP amount in a sample was determined using the aqueouslayer as the sample according to the method described in the [¹²⁵I]cAMPassay kit.

Also, with regard to the antagonistic activity (IC₅₀) of the testcompound, the IC₅₀ value was calculated as an inhibition rate based onthe reaction at 100 nM which was a concentration showing submaximal cAMPproduction by PGD₂ alone.

Toxicity:

The toxicity of the compound represented by formula (I) of the presentinvention is very low so that it is confirmed that the compound issufficiently safe for using as a pharmaceutical.

INDUSTRIAL APPLICABILITY

Application to Pharmaceuticals:

Since the compound represented by formula (I) in the present inventionbinds and is antagonistic to PGD₂ receptor, especially DP receptor, itis considered to be useful for the prevention and/or treatment ofdiseases, for example, allergic diseases (allergic rhinitis, allergicconjunctivitis, atopic dermatitis, bronchial asthma, food allergy,etc.), systemic mastocytosis, disorders due to systemic mastocyteactivation, anaphylactic shock, bronchoconstriction, urticaria, eczema,allergic bronchopulmonary aspergillosis, paranasal sinusitis, migraine,nasal polyp, hypersensitive angitis, eosinophilia, contact dermatitis,diseases accompanied with itching (such as atopic dermatitis, urticaria,allergic conjunctivitis, allergic rhinitis, contact dermatitis, etc.),secondary diseases (such as cataracta, retinodialysis, inflammation,infection, dysgryphia, etc.) generated by behaviors caused by itching(scratching behaviors, beating, etc.), inflammation, chronic obstructivepulmonary disease, ischemic reperfusion disorder, cerebrovasculardisorder, pleuritis complicated by rheumatoid arthritis, ulcerativecolitis and the like. Moreover, it is considered to relate to sleepingand platelet aggregation and to be useful for these diseases.

Since a compound that weakly binds with receptors other than DP receptordoesn't appear other actions, it is a possibility to become a medicinehaving a little side reaction.

Since the compound represented by formura (I) in the present inventionbinds to CRTH2 receptor and it expected to be antagonistic to thebiological activity, it is considered to be useful for the preventionand/or treatment of diseases, allergic diseases, for example, allergicrhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma,and food allergy, etc., systemic mastocytosis, disorders due to systemicmastocyte activation, bronchoconstriction, urticaria, eczema, psoriasis,allergic bronchopulmonary aspergillosis, paranasal sinusitis, nasalpolyp, hypersensitive angitis, eosinophilia, contact dermatitis,diseases accompanied with itching such as atopic dermatitis, urticaria,allergic conjunctivitis, allergic rhinitis, contact dermatitis, etc.,secondary diseases such as cataracta, retinodialysis, inflammation,infection, dysgryphia, etc. generated by behaviors caused by itching(scratching behaviors, beating, etc.), inflammation, chronic obstructivepulmonary disease, ischemic reperfusion disorder, cerebrovasculardisorder, pleuritis complicated by rheumatoid arthritis, osteoarthrosis,crohn disease, ulcerative colitis and the like.

The compound represented by formula (I) may be administered as otherconcomitant drug combining with other medicines, in order to

1) supplement and/or reinforce the prophylactic and/or therapeuticeffect of the compounds,

2) improve the movement and absorption of the compounds, and to decreasethe dosage, and/or

3) reduce the side effects of the compounds.

A combind drug with the compound represented by formula (I) and othermedicine may be administered in the compounding agent that mixes bothelements in a formulation or in the form administered as separateformulation. In the form administered as separate formulation, thedifferent and simultaneous administration are included. In the differentadministration, the compound represented by formula (I) may bepreviously administered, followed by other medicines, or other medicinesmay be previously administered, followed by the compound represented byformula (I). Each medication method may be different or same.

Illnesses that the prophylactic and/or therapeutic effects of the abovecombind drugs can be expected, which only has to be one that theprophylactic and/or therapeutic effects of the compound represented byformula (I) is/are supplemented and/or reinforced, are not limitedespecially.

As other medicines to supplement and/or reinforce the prophylacticand/or therapeutic effects of the compounds represented by the formula(I) on allergic rhinitis, for example, antihistamine agents, mediatorrelease inhibitors, thromboxane synthesis enzyme inhibitors, thromboxaneA2 receptor antagonists, leukotriene receptor antagonists, steroiddrugs, alpha-adrenergic receptor agonists, xanthine derivatives,cholinergic-blocking agents, and nitric oxide synthase inhibitors, etc.are included.

As other medicines to supplement and/or reinforce the prophylacticand/or therapeutic effects of the compounds represented by the formula(I) on allergic conjunctivitis, for example, leukotriene receptorantagonists, antihistamine agents, mediator release inhibitors,nonsteroidal anti-inflammatory drugs, prostaglandins, steroid drugs, andnitric oxide synthase inhibitors, etc. are included.

As antihistamine agents, for example, ketotifen fumarate, mequitazine,azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate,epinastine hydrochloride, astemizole, ebastine, cetirizinehydrochloride, bepotastine, fexofenadine, lolatadine, desloratadine,olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, mometasonefuroate, mizolastine, BP-294, andolast, auranofine, and acribastin, etc.are included.

As mediator release inhibitiors, for example, tranilast, sodiumcromoglycate, amlexanox, repirinast, ibudilast, tazanolast, andpemirolast potassium, etc. are included.

As thromboxane synthesis enzyme inhibitors, for example, ozagrelhydrochloride and imitrodast sodium, etc. are included.

As thromboxane A2 receptor antagonists, for example, seratrodast,ramatroban, domitroban calcium hydrate, and KT-2-962, etc. are included.

As leukotriene receptor antagonist, for example, pranlukast hydrate,montelukast, zafirlukast, MCC-847, KCA-757, CS-615, YM-158, L-740515,CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284, and ONO-4057,etc. are included.

In steroid drugs, for example, as drugs for external use, clobetasolpropionate, diflorazone diacetate, fluocinonide, mometasonefurancarboxylate, betamethasone dipropionate, betamethasone butyratepropionate, betamethasone valerate, difluprednate, budesonid,diflucortolone valerate, amcinonide, halcinonide, dexamethasone,dexamethasone propionate, dexamethason valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate-acetate,fluocinolone acetonide, beclometasone dipropionate, triamcinoloneacetonide, flumetasone pivalate, alclometasone propionate, clobetasonebutyrate, prednisolone, beclomethasone propionate, and fludroxycortide,etc. are included.

As internal medicines and injections, cortisone acetate, hydrocortisone,hydrocortisone sodium phosphate, hydrocortisone sodium succinate,fludrocortisone acetate, prednisolone, prednisolone acetate,prednisolone sodium succinate, prednisolone butylacetate, prednisolonesodium phosphate, halopredone acetate, methylprednisolone,methylprednisolone acetate, sodium methylprednisolone succinate,triamcinolone, triamcinolone diacetate, triamcinolone acetonide,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,dexamethasone palmitate, paramethasone acetate, and betamethasone, etc.are included.

As inhalants, beclometasone dipropionate, fluticasone propionate,budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide,dexamethasone palmitate, mometasone furancarboxylate, prasteronesulfonate, deflazacort, methylprednisolone suleptanate, andmethylprednisolone sodium succinate, etc. are included.

As xanthine derivatives, for example, aminophylline, theophylline,doxophylline, cipamfylline, and diprophylline, etc. are enumerated.

As cholilytic drugs, for example, ipratropium bromide, oxitropiumbromide, flutropium bromde, cimetropium bromide, temiverine, tiotropiumbromide, and revatropate (UK-112166), etc. are enumerated.

As non-steroidal anti-inflammatory drugs, for example, sasapyrine,sodiumsalicylate, aspirin, aspirin dialuminates combination, diflunisal,indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac,felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, nabumetone,puroglumetacine, indomethacin farnesyl, acemetacin, proglumetacinmaleate, amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofenpiconol, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen,fenoprofen calcium, tiaprofen, oxaprozin, pranoprofen, loxoprofensodium, aluminoprophen, zaltoprofen, mefenamic acid, mefenamic acidaluminum, tolfenamic acid, floctafenine, ketophenylbutazone,oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, napageln ointment,epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorfazonesulpyrine, migrenin, saridon, sedes G, amipylo-N, sorbon, pyrine drugfor common cold, acetaminophen, phenacetin, dimetotiazine mesilate,simetride combination drug, and non-pyrine drug for common cold, etc.are included.

As prostaglandins (hereafter, abbreviated with PG), PG receptor agonistsand PG receptor antagonist, etc. are included.

As PG receptor, PGE receptor (EP1, EP2, EP3, EP4), PGD receptor (DP,CRTH2), PGF receptor (FP), PGI receptor (IP), and TX receptor (TP), etc.are included.

Mass ratio of the compound represented by the formula (I) to othermedicine is not especially limited.

Other medicines may be administered combining with two arbitrary kindsor more.

In other medicines that supplement and/or reinforce prophylactic and/ortherapeutic effects of the compounds represented by the formula (I), notonly one that has been found by present according on the above mechanismbut also one that will be found in the future are included.

To use the compound represented by formula (I) or non-toxic saltthereof, or a combind drug containing the compound represented byformula (I) and other medicines by the above purpose, it is usuallyadministered systemically or locally, and orally or parenterally.

The dosage is determined depending on age, body weight, symptom,therapeutic effect, administration route, duration of the treatment andthe like. Generally, 1 mg to 1000 mg per adult is orally administeredonce to several times per day, or 1 mg to 100 mg per adult isparenterally administered (preferably, nose drop, ophthalmic solution,ointment) once to several times per day, or intravenously administeredfor 1 to 24 hours per day, continuously.

Since the dose changes depending on various conditions as describedabove, there are cases in which doses lower than or greater than theabove ranges may be used.

When the compound represented by the formula (I) or the combind drugcontaining it and other medicines are administered, they are used assolid medicines, liquid medicines, and other compositions for internaluse, and injections, external preparations, and suppositoriums, etc. forparenteral administration.

The solid compositions for oral administration include compressedtablets, pills, capsules, dispersing powders, granules, etc.

The capsules include hard capsules and soft capsules.

In such solid compositions, one or more active compound(s) is/are mixedwith at least one inert diluent such as lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate aluminate. The compositions mayalso contain additional substances other than inert diluents, forexample, lubricating agents such as magnesium stearate, disintegratingagents such as cellulose calcium glycolate, stabilizers such as lactoseand solubilizers such as glutamic acid or asparatic acid according tousual methods. The tablets or pills may, if desired, be coated with filmof gastric or enteric coating agents such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropyl cellulose phthalate, or becoated with two or more films. Furthermore, capsules of absorbablematerials such as gelatin are included.

The liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, syrups and elixirs. In such liquidcompositions, one or more active compound(s) is/are contained in inertdiluents commonly used (purified water and ethanol, etc.). Furthermore,these compositions may also contain wetting agents, adjuvants such assuspending agents, sweetening agents, flavoring agents, perfumingagents, and preserving agents besides inert diluents.

Other compositions for oral administration include sprays that areprepared by known methods, and one or more active compound(s). Thesecompositions may contain stabilizing agents such as sodium hydrogensulfate, buffers to give isotonicity, and isotonic solutions such assodium chloride, sodium citrate or citric acid besides inert diluents.Processes for preparing the sprays have been described in U.S. Pat. Nos.2,868,691 and 3,095,355.

The injections for parenteral administration include sterile aqueousand/or non-aqueous solutions, suspensions and emulsions. The aqueoussolutions or suspensions include, for example, distilled water forinjection and a physiological salt solution. The non-aqueous solutionsor suspensions include propylene glycol, polyethylene glycol, plant oilsuch as olive oil, alcohol such as ethanol, POLYSORBATE 80 (registeredtrade mark), and the like. They may be used mixing sterile aqueous ornon-aqueous solutions, suspensions and emulsions. These compositions maycontain preserving agents, wetting agents, emulsifying agents,dispersing agents, stabilizing agents (for example, lactose), andadjuvants such as solubilizer (glutamic acid and aspartic acid, etc.).These may be sterilized by filtrating through a bacteria-retainingfilter, mixing with antimicrobial agents, or irradiation. These may alsobe manufactured, for example, by making to be aseptic or dissolving toaseptic distilled water for injection or other solvents before use ofsterile solid compositions.

As dosage forms of the ophthalmic solution for parenteraladministration, ophthalmic solutions, ophthalmic suspensions, ophthalmicemulsions, ophthalmic solutions dissolved time of use, and ophthalmicointment are included.

These ophthalmic solutions are manufactured based on a well-knownmethod. For example, the ophthalmic solutions are made with tonicityagents (sodium chloride and concentrated glycerin, etc.), buffers(sodium phosphate and sodium acetate, etc.), surfactants (polysorbate 80(trade name), polyoxyl 40 stearate, and polyoxyethylene hydrogenatedcastor oil, etc.), stabilizers (sodium citrate and disodium edetate,etc.), and preservatives (benzalkonium chloride and paraben, etc.),etc., which are properly selected, if necessary. These are sterilized inthe final process or manufactured by the aseptic manipulation.

Inhalants for parenteral administration may include aerosol agents,inhalant powders or inhalant liquids, which may be used by beingdissolved or suspended in water or other suitable media before using.

The inhalants are manufactured acccording on a well-known method.

For example, inhalant liquids are prepared properly selecting, ifnecessary, preservatives (benzalkonium chloride and paraben, etc.),coloring agents, buffers (sodium phosphate and sodium acetate, etc.),tonicity agents (sodium chloride and concentrated glycerin, etc.),thickeners (carboxyvinyl polymer, etc.), and absorption enhancers, etc.

Inhalant powders are prepared properly selecting, if necessary,lubricants (stearic acid and the salt, etc.), binders (starch anddextrin, etc.), fillers (lactose and cellulose, etc.), coloring agents,preservatives (benzalkonium chloride and paraben, etc.), and absorptionenhancers, etc.

When the inhalant liquid is administered, a sprayer (atomizer andnebulizer) is usually used, and when the inhalant powder isadministered, an inhalation administering machine for powder is usuallyused.

As other compositions for parenteral administration, liquids forexternal use, ointments, liniments, suppositories for intrarectaladministration, and pessaries for administering in vagina, which containone or more activators and are prescribed with common procedure, areincluded.

BEST MODE FOR CARRYING OUT THE INVENTION

The following reference examples and examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parentheses in chromatographic separations or TLCshow the developing or eluting solvents and the ratio shows volumeratio. The solvents in the parentheses in NMR show the solvents formeasurement.

MS represents a trimethylsilyl group, and Bn represents a benzyl group.

Reference Example 1 N-formyl-2-fluoroaniline

Under argon gas, formate (6.1 mL) was added to acetic anhydride (15.5mL) at 0□ and the mixture was stirred at 50□ for 2 hours. The reactionmixture was cooled to room temperature and diluted with tetrahydrofuran(10 mL). Tetrahydrofuran (20 mL) solution containing 2-fluoroaniline(5.56 g) was added into the diluent at room temperature and stirred atroom temperature for 1 hour. A title compound having the followingphysical properties was obtained by concentrating the reaction mixture.The obtained title compound was used for the following reaction withoutfurther purification.

TLC:Rf 0.70(hexane:ethyl acetate=2:1).

Reference Example 2 N-methyl-2-fluoroaniline

Borane tetrahydrofuran complex (1 M tetrahydrofuran solution; 125 mL)were added into anhydrous tetrahydrofuran (25 mL) solution containingthe compound prepared according to reference example 1 at 0□, which wasstirred at 50□ for 2 hours. The reaction mixture was cooled to roomtemperature, in ice bath, methanol (30 mL) and 4N hydrogen chloridedioxane solution (10 mL) are added into the mixture and stirred at 60□for 1 hour. The reaction mixture was concentrated and added into 2Nsodium hydroxide solution, and then extracted with ethyl acetate. Theextract was washed with saturated brine and dried by sulfuric anhydridesodium. The solution was filtered by celite (registered trademark) andthe filtrate was concentrated. The mixed solvent (hexane:ethylacetate=10:1) was added to the residue, followed by be filtered onsilicagel. A title compound (6.45 g) having the following physicalproperties was obtained by concentrating the effluent.

TLC:Rf 0.85(hexane:ethyl acetate=5:1);

NMR(CDCl₃):δ 7.00-6.91 (m, 2H), 6.80-6.55 (m, 2H), 3.90 (br.s, 1H), 2.82(s, 3H).

Reference Example 3(2S)-3-(N-(2-fluorophenyl)-N-methylamino)-1,2-propanediol

Under argon gas, a mixture of the compound (1.24 g) prepared accordingto reference example 2, (R)-(+)-glycidol (1.11 g, made by aldrich and98% ee), and ethanol (1 mL) was stirred at 501 for 12 hours. Byconcentrating the reaction mixture, a title compound having thefollowing physical properties was obtained and used for the followingreaction without further purification.

TLC:Rf 0.40(hexane:ethyl acetate=1:1).

Reference Example 4(2S)-2-hydroxymethyl-4-methyl-3,4-dihydro-2H-1,4-benzoxazine

Potassium tert-butoxide (1.68 g) was added into anhydrous dimethylformamide (10 mL) solution containing the compound prepared according toreference example 3 in water bath and the mixture was stirred at 80□ at3 hours. The reaction mixture was added into water and extracted withethyl acetate. The extract was washed with saturated brine and dried bysulfuric anhydride sodium. The solution was filtered by celite(registered trademark) and the filtrate was concentrated. The residue ispurified by silica gel column chromatography (hexane:ethyl acetate=3:1)to give a title compound (1.55 g, 97.6% ee) having the followingphysical properties.

TLC:Rf 0.35(hexane:ethyl acetate=2:1);

NMR(CDCl₃):δ 7.90-6.79 (m, 2H), 6.70-6.60 (m, 2H), 4.33 (m, 1H), 3.82(dd, J=13.0, 4.2 Hz, 1H), 3.79 (dd, J=13.0, 4.2 Hz, 1H), 3.19 (dd,J=10.2, 2.1 Hz, 1H), 3.17 (dd, J=11.4, 5.4 Hz, 1H), 2.86 (s, 3H).

The optical purity of this title compound was decided by using highperformance liquid chromatography (HPLC).

A column: CHIRALCEL OD (Daicel Chemical Industries Ltd.)

-   -   0.46 cmφ×25 cm,        Flow rate: 1 ml/minute,        Solvent: Hexane:2-propanol=93:7,        Detection wave-length: 254 nm,        Retention time: 30.70 minutes,        Temperature: 24□.

Reference Example 5(2S)-2-mesyloxymethyl-4-methyl-3,4-dihydro-2H-1,4-benzoxazine

Triethylamine (23 mL) was added to the compound (20 g) preparedaccording to reference example 4 in toluene (80 mL) solution and themixture was cooled at 5□, methanesulfonyl chloride (9.5 mL) was droppedinto the solution, which was stirred for 30 minutes at 5□. The reactionmixture was added into water and extracted with ethyl acetate. Theextract was sequentially washed with water and saturated brine and driedby sulfuric anhydride sodium. The solution was filtered by celite. Thefiltrate was concentrated to give a title compound having the followingphysical properties. The obtained title compound was used for thefollowing reaction without further purification.

TLC:Rf 0.55(hexane:ethyl acetate=1:1);

NMR(CDCl₃):δ 6.88 (m, 1H), 6.81 (dd, J=8.4, 1.5 Hz, 1H), 6.75-6.65 (m,2H), 4.54 (m, 1H), 4.40 (d, J=5.4 Hz, 2H), 3.27 (dd, J=11.7, 2.7 Hz,1H), 3.17 (dd, J=11.7, 6.3 Hz, 1H), 3.07 (s, 3H), 2.88 (s, 3H).

Reference Example 64-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoic acidmethyl ester

Potassium carbonate (38.3 g) was added to dimethyl formamide (200 mL)solution containing the compound prepared according to reference example5 and 4-hydroxybenzoic acid methyl ester (23.2 g) at the roomtemperature and the mixture was stirred for 15 hours at 80□. Thereaction mixture was added into water and extracted with mixed solvent(ethyl acetate:hexane=1:2). The extract was sequentially washed with 1Nsodium hydroxide solution, water, and saturated brine, and dried bysulfuric anhydride sodium. The solution was filtered by celite. Thefiltrate was concentrated to give a title compound having the followingphysical properties. The obtained title compound was used for thefollowing reaction without further purification.

TLC:Rf 0.62(hexane:ethyl acetate=2:1);

NMR(CDCl₃):δ 7.99(d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.94-6.79(m, 2H), 6.70 (d, J=7.5 Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 4.65 (m, 1H),4.27 (dd, J=9.9, 4.8 Hz, 1H), 4.17 (dd, J=9.9, 6.6 Hz, 1H), 3.89 (s,3H), 3.39 (dd, J=11.7, 2.7 Hz, 1H), 3.25 (dd, J=11.7, 6.6 Hz, 1H), 2.90(s, 3H).

Reference Example 74-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoic acid

The compound prepared according to reference example 6 was dissolvedinto methanol (150 mL) and tetrahydrofuran (150 mL), 5N sodium hydroxidesolution (100 mL) in room temperature was added to the mixture, whichwas stirred for 15 hours at room temperature. The reaction mixture wasadded into water and washed with mixed solvent (ethylacetate:hexane=1:2). The crystal generated in the water layer acidifiedby 2N hydrochloric acid (260 mL) was acquired by filtration. The cakewas washed by water. A title compound (39 g) having the followingphysical properties was obtained by being dried for 2 days underdecompress.

TLC:Rf 0.13(hexane:ethyl acetate=2:1).

Reference Example 84-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoylchloride

Oxalylchloride (2.75 mL) was added to dimethoxyethane (21 mL) solutioncontaining the compound prepared according to reference example 7, whichwas stirred at 40□ for 1 hour. The reaction mixture was concentrated togive a title compound (4.7 g) having the following physical properties.

NMR(CDCl₃):δ 8.12 (d, J=8.7 Hz, 2H), 7.50 (dd, J=8.1, 1.5 Hz, 1H), 7.35(dt, J=1.5, 8.1 Hz, 1H), 7.16-6.95 (m, 4H), 5.07-4.96 (m, 1H), 4.52-4.40(m, 2H), 3.87 (dd, J=12.9, 2.1 Hz, 1H), 3.68 (dd, J=12.9, 10.5 Hz, 1H),3.29 (s, 3H).

Reference Example 9 2-(2-methylindol-3-yl)acetic acid benzyl ester

Under argon gas, potassium carbonate (2.52 g) and benzyl bromide (1.2mL) were added to dimethyl formamide (20 mL) solution containing2-(2-methylindol-3-yl)acetic acid (1.73 g), which was stirred at roomtemperature for 2 hours. The reaction mixture was radiationally cooledand water was added, and then the mixture was extracted by ethylacetate. The extract was sequentially washed with water and saturatedbrine and dried by sulfuric anhydride sodium, and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give a title compound (2.63 g) having the followingphysical properties was obtained.

TLC:Rf 0.52(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.83 (brs, 1H), 7.55-7.48 (m, 1H), 7.37-7.25(m, 6H),7.16-7.04 (m, 2H), 5.11 (s, 2H), 3.74 (s, 2H), 2.40 (s, 3H).

Example 12-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

Under argon gas, dichloromethane (5 mL) solution containingbenzyltriethylammonium chloride (82 mg) and the compound (1.52 g)preparedd according to reference example 8 were added to dichloromethane(5 mL) solution containing the compound (1 g) prepared according toreference example 9 and sodium hydroxide (716 mg) was added, and thenthe mixture was stirred at room temperature for 1 hour. Further, waterwas added to the reactive mixture, which was extracted by ethyl acetate.The extract was sequentially washed with water and saturated brine, anddried by sulfuric anhydride sodium, and then concentrated. The residuewas purified by silica gel column chromatography (toluene:ethylacetate=20:1) to give this invention compound (2 g) having the followingphysical properties.

TLC:Rf 0.63(toluene:ethyl acetate=9:1);

NMR(CDCl₃):δ 7.76-6.67 (m, 17H), 5.13 (s, 2H), 4.74-4.62 (m, 1H), 4.32(dd, J=9.9, 5.4 Hz, 1H), 4.21(dd, J=9.9, 6.3 Hz, 1H), 3.76 (s, 2H), 3.41(dd, J=11.7, 2.7 Hz, 1H), 3.28 (dd, J=11.4, 6.6 Hz, 1H), 2.92 (s, 3H),2.40 (s, 3H).

Example 22-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

Under argon gas, 20% hydroxide palladium (100 mg) was added to ethylacetate (20 mL) solution containing the compound (2 g) preparedaccording to example 1 and after hydrogen replacement, the mixture wasstirred for 80 minutes at room temperature. The reaction mixture wasfiltered by celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography (chloroform:methanol=20:1)to give the compound (380 mg) of the present invention having thefollowing physical properties.

TLC:Rf 0.42(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.73 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.17 (dt,J=1.5, 8.1 Hz, 1H), 7.09-6.94 (m, 4H), 6.93-6.81 (m, 2H), 6.75-6.66 (m,2H), 4.74-4.64 (m, 1H), 4.32 (dd, J=9.9, 5.1 Hz, 1H), 4.21 (dd, J=9.9,6.3 Hz, 1H), 3.75 (s, 2H), 3.41 (dd, J=11.7, 2.4 Hz, 1H), 3.28 (dd,J=11.7, 6.6 Hz, 1H), 2.93 (s, 3H), 2.43 (s, 3H).

Example 3(1) to Example 3 (12)

Using 2-(2-methylindol-3-yl)acetic acid or the corresponding carboxylicacid derivative, and the compound prepared according to referenceexample 8 or a corresponding acid halide derivative, the followingcompounds of the present invention were obtained by carrying out anoperation similar to a method sequentially represented by referenceexample 9, example 1, and example 2.

Example 3(1)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid

TLC:Rf 0.42(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.71 (d, J=8.7 Hz, 2H), 7.04-6.94 (m, 3H), 6.94-6.80 (m,3H), 6.76-6.62 (m, 3H), 4.74-4.64 (m, 1H), 4.31 (dd, J=9.6, 5.1 Hz, 1H),4.21 (dd, J=9.6, 6.0 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 2H), 3.41 (dd,J=11.7, 2.4 Hz, 1H), 3.28 (dd, J=11.7, 6.3 Hz, 1H), 2.91 (s, 3H), 2.42(s, 3H).

Example 3(2)3-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)propanoicacid

TLC:Rf 0.49(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.71 (d, J=8.7 Hz, 2H), 7.48 (d, J=7.5 Hz, 1H), 7.20-7.12(m, 1H), 7.08-6.94 (m, 4H), 6.92-6.81 (m, 2H), 6.76-6.66 (m, 2H),4.74-4.60 (m, 1H), 4.31 (dd, J=9.9, 5.1 Hz, 1H), 4.21 (dd, J=9.9, 6.3Hz, 1H), 3.41 (dd, J=11.4, 2.7 Hz, 1H), 3.28 (dd, J=11.4, 6.6 Hz, 1H),3.07 (t, J=8.1 Hz, 2H), 2.92 (s, 3H), 2.70 (t, J=8.1 Hz, 2H), 2.40 (s,3H).

Example 3(3)2-(1-(4-propoxymethylbenzoyl)-2-methyl-5-methoxyindol-3-yl)acetic acid

TLC:Rf 0.53(chloroform:methanol=8:2);

NMR(CDCl₃):δ 7.71-7.68 (m, 2H), 7.47-7.44 (m, 2H), 6.95 (d, J=2.0 Hz,1H), 6.88 (d, J=9.0 Hz, 1H), 6.65 (dd, J=9.0, 2.0 Hz, 1H), 4.61 (s, 2H),3.82 (s, 3H), 3.70 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 2.38 (s, 3H), 1.68(tq, J=6.5, 7.0 Hz, 2H), 0.97 (J=7.0 Hz, 3H).

Example 3(4)2-(1-(4-(2-ethoxyethyl)benzoyl)-2-methyl-5-methoxyindol-3-yl)acetic acid

TLC:Rf 0.35(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.66-7.63 (m, 2H), 7.36-7.33 (m, 2H), 6.95 (d, J=1.5 Hz,1H), 6.98 (d, J=6.0 Hz, 1H), 6.65 (dd, J=6.0, 1.5 Hz, 1H), 3.83 (s, 3H),3.70 (s, 2H), 3.69 (t, J=4.5 Hz, 2H), 3.51 (q, J=4.5 Hz, 2H), 2.98 (t,J=4.5 Hz, 2H), 2.38 (s, 2H), 1.20 (t, J=4.5 Hz, 3H).

Example 3(5) 2-(1-(4-phenoxybenzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid

TLC:Rf 0.51(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.70 (d, J=9.0 Hz, 2H), 7.46-7.37 (m, 2H), 7.25-7.18 (m,1H), 7.14-7.08 (m, 2H), 7.02 (d, J=9.0 Hz, 2H), 6.97-6.91 (m, 2H), 6.69(dd, J=9.0, 2.4 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 2H), 2.41 (s, 3H).

Example 3(6)2-(1-(4-benzyloxybenzoyl)-2-methyl-5-methoxyindol-3-yl)acetic acid

TLC:Rf 0.60(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.71 (d, J=8.7 Hz, 2H), 7.48-7.32 (m, 5H), 7.03 (d, J=8.7Hz, 2H), 6.95 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.66 (dd,J=9.0, 2.4 Hz, 1H), 5.15 (s, 2H), 3.83 (s, 3H), 3.71 (s, 2H), 2.41 (s,3H).

Example 3(7)2-(1-(4-(2-phenylethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid

TLC:Rf 0.54(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.68 (d, J=8.7 Hz, 2H), 7.38-7.22 (m, 5H), 6.98-6.90 (m,3H), 6.87 (d, J=9.0 Hz, 1H), 6.65 (dd, J=9.0, 2.7 Hz, 1H), 4.26 (t,J=6.9 Hz, 2H), 3.82 (s, 3H), 3.70 (s, 2H), 3.14 (t, J=6.9 Hz, 2H), 2.40(s, 3H).

Example 3(8)2-(1-(4-(2-methoxyethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid

TLC:Rf 0.23(methanol:chloroform=1:10);

NMR(CDCl₃):δ 7.69 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.95 (d,J=2.6 Hz, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.65 (dd, J=9.0, 2.6 Hz, 1H),4.20 (m, 2H), 3.83 (s, 3H), 3.80 (m, 2H), 3.71 (s, 2H), 3.46 (s, 3H),2.41 (s, 3H).

Example 3(9)2-(1-(4-(2-ethoxyethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid

TLC:Rf 0.25(chloroform:methanol=1:10);

NMR(CDCl₃):δ 7.69 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.95 (d,J=2.8 Hz, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.65 (dd, J=9.0, 2.8 Hz, 1H),4.21 (m, 2H), 3.86-3.78 (m, 2H), 3.83 (s, 3H), 3.70 (s, 2H), 3.62 (q,J=7.0 Hz, 2H), 2.41 (s, 3H), 1.26 (t, J=7.0 Hz, 3H).

Example 3(10)2-(1-(3-(2-phenylethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid

TLC:Rf 0.51(chloroform:methanol=10:1);

NMR(DMSO-d₆):δ 8.72 (s, 1H), 7.89-7.82 (m, 3H), 7.80 (s, 1H), 7.71-7.61(m, 2H), 7.52-7.42 (m, 3H), 7.30-7.23 (m, 2H), 7.07 (s, 1H), 7.06 (d,J=7.5 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 5.46 (s, 2H), 4.22 (t, J=6.6 Hz,2H), 3.18 (t, J=6.6 Hz, 2H), 2.69 (t, J=8.1 Hz, 2H), 2.34 (t, J=8.1 Hz,2H).

Example 3(11)2-(1-(3-(2-ethoxyethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=10:1);

NMR(CDCl₃):δ 7.84-7.76 (m, 3H), 7.75 (s, 1H), 7.49-7.38 (m, 3H), 7.06(d, J=6.9 Hz, 1H), 6.78-6.70 (m, 2H), 4.29 (s, 2H), 4.26 (t, J=6.3 Hz,2H), 3.36-3.22 (m, 2H), 3.26 (t, J=6.3 Hz, 2H), 3.19-3.09 (m, 2H), 2.88(t, J=7.8 Hz, 2H), 2.82 (s, 3H), 2.52 (t, J=7.8 Hz, 2H).

Example 3(12)2-(1-(4-(3-phenylpropoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid

TLC:Rf 0.35(ethyl acetate);

NMR(DMSO-d₆):δ 12.02 (s, 1H), 9.47 (s, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.94(d, J=7.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.73 (dd, J=6.6, 2.1 Hz, 1H),7.60-7.46 (m, 4H), 7.42-7.34 (m, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.12 (d,J=8.1 Hz, 1H), 7.02 (dd, J=8.1, 1.8 Hz, 1H), 6.38 (d, J=9.0 Hz, 1H),6.20 (dt, J=1.5, 6.6 Hz, 1H), 5.01 (s, 2H), 4.69-4.64 (m, 1H), 2.40-2.35(m, 2H), 1.99 (t, J=7.5 Hz, 2H), 1.59-1.50 (m, 5H).

Reference Example 10 2-(1-(4-acetyloxybenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

Uner argon gas, dichloromethane (24 mL) solution containingbenzyltriethylammonium chloride (281 mg) and 4-acetyloxybenzoyl chloride(3.68 g) was added to dichloromethane (100 mL) solution containing thecompound (3.45 g) prepared according to reference example 9 and sodiumhydroxide (2.47 g) was added, and then the mixture was stirred for 40minutes at room temperature. The reactive mixture was filtered withcelite, and the filtrate was used for the following reaction as it was.

TLC:Rf 0.49(hexane:ethyl acetate=7:3).

Reference Example 11 2-(1-(4-hydroxybenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

Piperidine (3.46 mL) was added to the filtrate prepared according toreference example 10 at room temperature, which was stirred for 1.5hours at room temperature. Water is added to the reactive mixture, whichwas separated. The organic layer was sequentially washed with water andsaturated brine, and dried by sulfuric anhydride sodium, andconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=7:3) to give a title compound (3 g)having the following physical properties.

TLC:Rf 0.24(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.66 (d, J=9.0 Hz, 2H), 7.49 (d, J=7.5 Hz, 1H), 7.38-7.26(m, 5H), 7.15 (dt, J=1.8, 7.5 Hz, 1H), 7.10-6.97 (m, 2H), 6.88 (d, J=9.0Hz, 2H), 5.15 (s, 2H), 3.76 (s, 2H), 2.40 (s, 3H).

Example 42-(1-(4-((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

Under argon gas, triphenylphosphine (216 mg) was added totetrahydrofuran (3 mL) solution containing the compound (100 mg)prepared according to reference example 11 and(2S)-2-hydroxymethyl-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazines (64.2mg) and diethylazodicarboxylate (0.38 mL; 40% toluene solution) wasdropped to the mixture, which was stirred for 40 minutes at roomtemperature. The reactive mixture was concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give a title compound (50 mg) having the following physicalproperties.

TLC:Rf 0.50(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.71 (d, J=8.7 Hz, 2H), 7.50 (d, J=8.1 Hz, 1H), 7.40-7.24(m, 5H), 7.15 (t, J=6.9 Hz, 1H), 7.09-6.96 (m, 4H), 6.73-6.60 (m, 3H),5.14 (s, 2H), 4.72-4.63 (m, 1H), 4.30 (dd, J=9.9, 4.8 Hz, 1H), 4.21 (dd,J=9.9, 6.0 Hz, 1H), 3.76 (s, 2H), 3.36 (dd, J=11.4, 2.7 Hz, 1H), 3.22(dd, J=11.4, 6.6 Hz, 1H), 2.88(s, 3H), 2.40 (s, 3H), 2.23 (s, 3H).

Example 52-(1-(4-((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

Using the compound prepared according to example 4 instead of thecompound prepared according to example 1, the compound of the presentcompound having the following physical properties was obtained by theoperation similar to example 2.

TLC:Rf 0.26(hexane:ethyl acetate=1:1);

NMR(CDCl₃):δ 7.73 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.17 (t,J=6.9 Hz, 1H), 7.09-6.92 (m, 4H), 6.74-6.60 (m, 3H), 4.72-4.63 (m, 1H),4.30 (dd, J=9.9, 4.8 Hz, 1H), 4.21 (dd, J=9.9, 6.0 Hz, 1H), 3.75 (s,2H), 3.36 (dd, J=11.4, 2.7 Hz, 1H), 3.22 (dd, J=11.4, 6.6 Hz, 1H),2.88(s, 3H), 2.43 (s, 3H), 2.23 (s, 3H).

Example 6 (1) to Example 6 (10)

This following invention compounds were obtained by the operation fromexample 4 to example 2 using the corresponding alcoholic derivativeinstead of(2S)-2-hydroxymethyl-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazine.

Example 6(1)2-(1-(4-((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.27(hexane:ethyl acetate=1:1);

NMR(CDCl₃):δ 7.73 (d, J=8.7 Hz, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.17 (t,J=7.8 Hz, 1H), 7.10-6.92 (m, 4H), 6.73 (d, J=7.8 Hz, 1H), 6.55-6.45 (m,2H), 4.70-4.60 (m, 1H), 4.30 (dd, J=10.2, 4.8 Hz, 1H), 4.20 (dd, J=10.2,6.3 Hz, 1H), 3.75 (s, 2H), 3.39 (dd, J=11.7, 2.7 Hz, 1H), 3.26 (dd,J=11.7, 6.6 Hz, 1H), 2.90 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H).

Example 6(2)2-(1-(4-((3R)-5-fluoro-2,3-dihydrobenzofuran-3-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.22(hexane:ethyl acetate=1:1);

NMR(CDCl₃):δ 7.72 (d, J=8.7 Hz, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.21-7.11(m, 2H), 7.05 (t, J=7.8 Hz, 1H), 7.01-6.93 (m, 3H), 6.68-6.56 (m, 2H),4.76 (t, J=9.3 Hz, 1H), 4.68 (dd, J=9.3, 3.9 Hz, 1H), 4.46-4.40 (m, 1H),4.20-4.06 (m, 2H), 3.74 (s, 2H), 2.42 (s, 3H).

Example 6(3)2-(1-(4-(2,3-dihydrobenzofuran-3-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.16(hexane:ethyl acetate=1:1);

NMR(CDCl₃):δ 7.73 (d, J=9.0 Hz, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.31 (d,J=7.8 Hz, 1H), 7.24-7.13 (m, 2H), 7.04 (t, J=7.8 Hz, 1H), 7.01-6.83 (m,5H), 4.73 (t, J=9.0 Hz, 1H), 4.55 (dd, J=9.0, 5.1 Hz, 1H), 4.24 (dd,J=9.0, 5.7 Hz, 1H), 4.11 (t, J=9.0 Hz, 1H), 4.04-3.92 (m, 1H), 3.75 (s,2H), 2.43 (s, 3H).

Example 6(4)2-(1-(4-(2-(6-methylpyridin-2-yl)ethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.54(ethyl acetate:methanol=10:1);

NMR(CDCl₃):δ 7.63 (d, J=8.1 Hz, 2H), 7.55 (dd, J=7.8, 7.5 Hz, 1H), 7.53(d, J=7.8 Hz, 1H), 7.17-6.93 (m, 5H), 6.84 (d, J=8.1 Hz, 2H), 4.31 (t,J=6.6 Hz, 2H), 3.71 (s, 2H), 3.24 (t, J=6.6 Hz, 2H), 2.56 (s, 3H), 2.40(s, 3H).

Example 6(5)2-(1-(4-(2-(3-methylpyridin-2-yl)ethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(ethyl acetate:methanol=10:1);

NMR(CDCl₃):δ 8.43 (d, J=4.5 Hz, 1H), 7.70-7.49 (m, 4H), 7.16-7.10 (m,2H), 7.01 (m, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H), 4.37(t, J=6.6 Hz, 2H), 3.71 (s, 2H), 3.30 (t, J=6.6 Hz, 2H), 2.41 (s, 3H),2.41 (s, 3H).

Example 6(6)2-(1-(4-((2R)-1,4-benzodioxan-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.57(ethyl acetate);

NMR(CDCl₃):δ 7.77-7.70 (m, 2H), 7.50 (d, J=7.5 Hz, 1H), 7.17 (m, 1H),7.08-6.85 (m, 8H), 4.61 (m, 1H), 4.42 (dd, J=11.4, 2.1 Hz, 1H), 4.33(dd, J=10.2, 5.1 Hz, 1H), 4.26 (dd, J=11.4, 6.3 Hz, 1H), 4.25 (dd,J=10.2, 6.3 Hz, 1H), 3.74 (s, 2H), 2.42 (s, 3H).

Example 6(7)2-(1-(4-(1,3-dioxanindan-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.60(ethyl acetate);

NMR(CDCl₃):δ 7.73 (d, J=8.4 Hz, 2H), 7.50 (d, J=7.8 Hz, 1H), 7.17 (dd,J=7.8, 7.2 Hz, 1H), 7.06-6.93 (m, 4H), 6.86 (s, 4H), 6.49 (t, J=3.9 Hz,1H), 4.35 (d, J=3.9 Hz, 2H), 3.73 (s, 2H), 2.42 (s, 3H).

Example 6(8)2-(1-(4-((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.49(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.74 (d, J-=9.0 Hz, 2H), 7.51 (d, J=7.5 Hz, 1H), 7.18 (dt,J=1.2, 7.5 Hz, 1H), 7.08-6.94 (m, 3H), 6.64-6.56 (m, 3H), 4.85-4.75 (m,1H), 4.30 (dd, J=9.9, 5.1 Hz, 1H), 4.21 (dd, J=9.9, 6.0 Hz, 1H), 3.75(s, 2H), 3.36 (dd, J=11.7, 2.7 Hz, 1H), 3.22 (dd, J=11.7, 6.6 Hz, 1H),2.88(s, 3H), 2.43 (s, 3H).

Example 6(9)2-(1-(4-((2S)-2,3-dihydrobenzofuran-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.37(chloroform:methanol=10:1);

NMR(CDCl₃):δ 7.74-7.69 (m, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.24-7.11 (m,3H), 7.06-6.81 (m, 6H), 5.19 (m, 1H), 4.29 (dd, J=9.9, 6.3 Hz, 1H), 4.20(dd, J=9.9, 4.2 Hz, 1H), 3.73 (s, 2H), 3.42 (dd, J=16.2, 9.6 Hz, 1H),3.17 (dd, J=16.2, 7.2 Hz, 1H), 2.41 (s, 3H).

Example 6(10)2-(1-(4-((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.50(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.73 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.17 (dt,J=1.5, 8.1 Hz, 1H), 7.08-6.94 (m, 4H), 6.70-6.62 (m, 1H), 6.52-6.44 (m,2H), 4.74-4.65 (m, 1H), 4.31 (dd, J=9.9, 5.1 Hz, 1H), 4.22 (dd, J=9.9,6.0 Hz, 1H), 3.74 (s, 5H), 3.33 (dd, J=11.7, 2.7 Hz, 1H), 3.18 (dd,J=11.7, 6.6 Hz, 1H), 2.86 (s, 3H), 2.42 (s, 3H).

Example 7(1) to Example 7(40)

Using the compound prepared according to reference example 9 or thesubstitute derivative and the compound prepared according to referenceexample 8 or the substitute derivative, this following inventioncompounds were obtained by the operation similar to example 1.

Example 7(1)(2E)-4-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)-2-butenoicacid benzyl ester

TLC:Rf 0.41(hexane:ethyl acetate=7:3).

Example 7(2)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.46(hexane:ethyl acetate=1:1).

Example 7(3)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.46(hexane:ethyl acetate=1:1).

Example 7(4)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.81(hexane:ethyl acetate=2:1).

Example 7(5)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-trifluoromethyl-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.81(hexane:ethyl acetate=2:1).

Example 7(6)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.48(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.40-7.25 (m, 7H), 7.20-7.00 (m,3H), 6.93-6.76 (m, 3H), 6.75-6.67 (m, 2H), 5.13 (s, 2H), 4.73-4.63 (m,1H), 4.29 (dd, J=9.6, 4.8 Hz, 1H), 4.18 (dd, J=9.6, 6.3 Hz, 1H), 3.74(s, 2H), 3.41 (dd, J=11.4, 2.7 Hz, 1H), 3.28 (dd, J=11.4, 6.6 Hz, 1H),2.92 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H).

Example 7(7)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.31(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.40-7.24 (m, 6H), 7.00-6.76 (m, 6H), 6.76-6.64 (m, 3H),5.13 (s, 2H), 4.74-4.62 (m, 1H), 4.28 (dd, J=9.6, 5.1 Hz, 1H), 4.18 (dd,J=9.6, 6.3 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 2H), 3.41 (dd, J=11.7, 2.7Hz, 1H), 3.28 (dd, J=11.7, 6.6 Hz, 1H), 2.92 (s, 3H), 2.29 (s, 3H), 2.27(s, 3H).

Example 7(8)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.30(hexane:ethyl acetate=7:3).

Example 7(9)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.52(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.45 (d, J=2.1 Hz, 1H), 7.39-7.23 (m, 6H), 7.02-6.76 (m,6H), 6.75-6.66 (m, 2H), 5.14 (s, 2H), 4.72-4.62 (m, 1H), 4.28 (dd,J=9.9, 5.4 Hz, 1H), 4.18 (dd, J=9.9, 6.6 Hz, 1H), 3.69 (s, 2H), 3.41(dd, J=11.1, 2.4 Hz, 1H), 3.28 (dd, J=11.1, 6.6 Hz, 1H), 2.92 (s, 3H),2.29 (s, 6H).

Example 7(10)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.48(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.40-7.24 (m, 6H), 7.13 (dd, J=8.7, 2.4 Hz, 1H), 7.03 (dd,J=9.0, 4.8 Hz, 1H), 6.92-6.75 (m, 5H), 6.75-6.67 (m, 2H), 5.13 (s, 2H),4.73-4.63 (m, 1H), 4.28 (dd, J=9.9, 4.8 Hz, 1H), 4.18 (dd, J=9.9, 6.3Hz, 1H), 3.68 (s, 2H), 3.41 (dd, J=11.4, 2.1 Hz, 1H), 3.28 (dd, J=11.4,6.6 Hz, 1H), 2.92 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H).

Example 7(11)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.42(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.54-7.40 (m, 2H), 7.40-7.03 (m, 9H), 6.97-6.82 (m, 3H),6.75-6.67 (m, 2H), 5.12 (s, 2H), 4.72-4.64 (m, 1H), 4.29 (dd, J=9.9, 4.8Hz, 1H), 4.20 (dd, J=9.9, 6.0 Hz, 1H), 3.73 (s, 2H), 3.40 (dd, J=12.0,2.7 Hz, 1H), 3.27 (dd, J=12.0, 6.0 Hz, 1H), 2.92 (s, 3H), 2.30 (s, 3H).

Example 7(12)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,3-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.57(hexane:ethyl acetate=2:1);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.35-7.27 (m, 5H), 7.19-7.14 (m,2H), 7.10-7.03 (m, 2H), 6.92-6.83 (m, 2H), 6.77-6.67 (m, 3H), 5.13 (s,2H), 4.72-4.67 (m, 1H), 4.30-4.08 (m, 2H), 3.74 (s, 2H), 3.45-3.29 (m,2H), 2.93 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H).

Example 7(13)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.50(hexane:ethyl acetate=2:1);

NMR(CDCl₃):δ 7.61 (d, J=2.1 Hz, 1H), 7.54 (dd, J=8.1, 2.1 Hz, 1H), 7.50(d, J=7.8 Hz, 1H), 7.34-7.29 (m, 5H), 7.19-7.14 (m, 2H), 7.15 (dt,J=7.8, 2.1 Hz, 1H), 7.10-6.98 (m, 2H), 5.14 (s, 2H), 4.75-4.65 (m, 1H),4.34-4.17 (m, 2H), 3.76 (s, 2H), 3.45-3.28 (m, 2H), 2.92 (s, 3H), 2.40(s, 3H), 2.27 (s, 3H).

Example 7(14)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.58(toluene:ethyl acetate=9:1);

NMR(CDCl₃):δ 7.36-7.23 (m, 6H), 6.96-6.76 (m, 7H), 6.76-6.66 (m, 2H),5.13 (s, 2H), 4.72-4.62 (m, 1H), 4.28 (dd, J=9.9, 5.4 Hz, 1H), 4.17 (dd,J=9.9, 6.0 Hz, 1H), 3.71 (s, 2H), 3.41 (dd, J=12.0, 3.0 Hz, 1H), 3.28(dd, J=12.0, 6.6 Hz, 1H), 2.92 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H), 2.27(s, 3H).

Example 7(15)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methoxybenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.38(hexane:ethyl acetate=2:1);

NMR(CDCl₃):δ 7.50 (d, J=8.1 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.33-7.26(m, 6H), 7.18-7.03 (m, 3H), 6.94-6.82 (m, 3H), 6.72-6.67 (m, 2H), 5.14(s, 2H), 4.78-4.70 (m, 1H), 4.38-4.22 (m, 2H), 3.87 (s, 3H), 3.76 (s,2H), 3.43 (dd, J=11.4, 2.7 Hz, 1H), 3.30 (dd, J=11.4, 6.6 Hz 1H), 2.91(s, 3H), 2.41(s, 3H).

Example 7(16)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-fluorobenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.30(hexane:ethyl acetate=3:1);

NMR(CDCl₃):δ 7.56-6.68 (m, 16H), 5.14 (s, 2H), 4.76-4.65 (m, 1H),4.40-4.25 (m, 2H), 3.75 (s, 2H), 3.45-3.28 (m, 2H), 2.92 (s, 3H), 2.40(s, 3H).

Example 7(17)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methoxybenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.37(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.55-7.00 (m, 10H), 6.95-6.80 (m, 2H), 6.76-6.65 (m, 2H),6.62-6.47 (m, 2H), 5.12 (s, 2H), 4.72-4.62 (m, 1H), 4.30 (dd, J=9.9, 5.1Hz, 1H), 4.20 (dd, J=9.9, 6.0 Hz, 1H), 3.73 (s, 2H), 3.58 (s, 3H), 3.41(dd, J=12.0, 2.7 Hz, 1H), 3.29 (dd, J=12.0, 6.3 Hz, 1H), 2.93 (s, 3H),2.32 (s, 3H).

Example 7(18)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-chlorobenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.49(hexane:ethyl acetate=2:1).

Example 7(19)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.53(hexane:ethyl acetate=2:1);

NMR(CDCl₃):δ 7.56-7.47 (m, 3H), 7.34-7.26 (m, 4H), 7.21-7.05 (m, 3H),6.92-6.82 (m, 3H), 6.74-6.68 (m, 3H), 5.13 (s, 2H), 4.72-4.64 (m, 1H),4.32-4.09 (m, 2H), 3.74 (s, 2H), 3.42-3.25 (m, 2H), 2.92 (s, 3H), 2.38(s, 3H).

Example 7(20)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.54(toluene:ethyl acetate=9:1);

NMR(CDCl₃):δ 7.59 (brs, 1H), 7.53 (dd, J=8.7, 2.4 Hz, 1H), 7.37-7.24 (m,6H), 6.96-6.81 (m, 5H), 6.76-6.66 (m, 2H), 5.14 (s, 2H), 4.75-4.65 (m,1H), 4.31 (dd, J=9.9, 4.8 Hz, 1H), 4.22 (dd, J=9.9, 6.0 Hz, 1H), 3.73(s, 2H), 3.42 (dd, J=11.1, 2.4 Hz, 1H), 3.32 (dd, J=11.1, 6.0 Hz, 1H),2.93 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H).

Example 7(21)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.55(toluene:ethyl acetate=9:1);

NMR(CDCl₃):δ 7.60-7.56 (m, 1H), 7.51 (dd, J=8.7, 2.7 Hz, 1H), 7.38-7.27(m, 5H), 7.14 (dd, J=9.0, 2.7 Hz, 1H), 6.95 (dd, J=9.0, 4.5 Hz, 1H),6.93-6.67 (m, 6H), 5.15 (s, 2H), 4.74-4.65 (m, 1H), 4.31 (dd, J=9.9, 5.1Hz, 1H), 4.22 (dd, J=9.9, 6.3 Hz, 1H), 3.71 (s, 2H), 3.42 (dd, J=11.4,2.7 Hz, 1H), 3.31 (dd, J=11.4, 6.6 Hz, 1H), 2.92 (s, 3H), 2.37 (s, 3H),2.27 (s, 3H).

Example 7(22)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.57(toluene:ethyl acetate=9:1);

NMR(CDCl₃):δ 7.60-7.45 (m, 3H), 7.41-7.24 (m, 5H), 7.04-6.81 (m, 5H),6.76-6.66 (m, 2H), 5.12 (s, 2H), 4.75-4.66 (m, 1H), 4.32 (dd, J=9.6, 4.8Hz, 1H), 4.23 (dd, J=9.6, 6.3 Hz, 1H), 3.69 (s, 2H), 3.42 (dd, J=11.4,2.7 Hz, 1H), 3.31 (dd, J=11.4, 6.3 Hz, 1H), 2.93 (s, 3H), 2.39 (s, 3H),2.27 (s, 3H).

Example 7(23)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.50(toluene:ethyl acetate=9:1);

NMR(CDCl₃):δ 7.60-7.50 (m, 2H), 7.37-7.27 (m, 5H), 6.95-6.81 (m, 5H),6.76-6.62 (m, 3H), 5.14 (s, 2H), 4.75-4.65 (m, 1H), 4.32 (dd, J=9.9, 5.1Hz, 1H), 4.22 (dd, J=9.9, 6.3 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 2H), 3.42(dd, J=11.7, 3.0 Hz, 1H), 3.32 (dd, J=11.7, 6.3 Hz, 1H), 2.93 (s, 3H),2.39 (s, 3H), 2.26 (s, 3H).

Example 7(24)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,3-dimethylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.54(hexane:ethyl acetate=2:1).

Example 7(25)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methoxybenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.55(hexane:ethyl acetate=2:1).

Example 7(26)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-fluorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.55(hexane:ethyl acetate=2:1).

Example 7(27)2-(1-(3-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.61(toluene:ethyl acetate=9:1);

NMR(CDCl₃):δ 7.54-7.46 (m, 1H), 7.40-7.00 (m, 12H), 6.90-6.79 (m, 2H),6.74-6.63 (m, 2H), 5.14 (s, 2H), 4.68-4.58 (m, 1H), 4.25 (dd, J=9.6, 5.1Hz, 1H), 4.15 (dd, J=9.6, 6.3 Hz, 1H), 3.75 (s, 2H), 3.37 (dd, J=11.7,2.7 Hz, 1H), 3.24 (dd, J=11.7, 6.9 Hz, 1H), 2.89 (s, 3H), 2.41 (s, 3H).

Example 7(28)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.48(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.42 (d, J=8.4 Hz, 1H), 7.40-7.10 (m, 7H), 7.04 (d, J=2.7Hz, 1H), 6.98-6.80 (m, 4H), 6.76-6.68 (m, 2H), 5.13 (s, 2H), 4.73-4.63(m, 1H), 4.29 (dd, J=9.6, 5.4 Hz, 1H), 4.20 (dd, J=9.6, 5.7 Hz, 1H),3.67 (s, 2H), 3.40 (dd, J=11.1, 2.4 Hz, 1H), 3.27 (dd, J=11.1, 6.3 Hz,1H), 2.92 (s, 3H), 2.24 (s, 3H).

Example 7(29)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.45(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47-7.40 (m, 2H), 7.40-7.24 (m, 5H), 7.20-7.00 (m, 3H),6.98-6.82 (m, 3H), 6.76-6.67 (m, 2H), 5.13 (s, 2H), 4.73-4.63 (m, 1H),4.29 (dd, J=9.9, 4.8 Hz, 1H), 4.20 (dd, J=9.9, 5.7 Hz, 1H), 3.68 (s,2H), 3.40 (dd, J=11.7, 2.7 Hz, 1H), 3.27 (dd, J=11.7, 6.3 Hz, 1H), 2.92(s, 3H), 2.26 (s, 3H).

Example 7(30)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.52(toluene:ethyl acetate=9:1).

Example 7(31)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.49(hexane:ethyl acetate=2:1).

Example 7(32)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.55(hexane:ethyl acetate=2:1).

Example 7(33)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.49(hexane:ethyl acetate=2:1).

Example 7(34)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.74(hexane:ethyl acetate=2:1).

Example 7(35)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.44(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.44-7.20 (m, 6H), 7.07-6.80 (m, 7H), 6.76-6.65 (m, 2H),5.12 (s, 2H), 4.72-4.62 (m, 1H), 4.28 (dd, J=9.9, 5.4 Hz, 1H), 4.19 (dd,J=9.9, 6.0 Hz, 1H), 3.70 (s, 2H), 3.40 (dd, J=11.7, 2.7 Hz, 1H), 3.27(dd, J=11.7, 6.6 Hz, 1H), 2.92 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H).

Example 7(36)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.49(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.56-7.24 (m, 8H), 7.18-6.96 (m, 3H), 6.91-6.80 (m, 2H),6.76-6.66 (m, 2H), 5.15 (s, 2H), 4.74-4.64 (m, 1H), 4.10-4.00 (m, 2H),3.76 (s, 2H), 3.44 (dd, J=11.4, 2.7 Hz, 1H), 3.34 (dd, J=11.4, 6.3 Hz,1H), 2.93 (s, 3H), 2.38 (s, 3H), 2.32 (s, 6H).

Example 7(37)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-trifluoromethoxy-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.48(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.38-7.25 (m, 7H), 7.06 (d, J=9.0 Hz, 1H), 6.96-6.76 (m,5H), 6.75-6.66 (m, 2H), 5.13 (s, 2H), 4.72-4.62 (m, 1H), 4.29 (dd,J=9.9, 5.1 Hz, 1H), 4.18 (dd, J=9.9, 6.3 Hz, 1H), 3.71 (s, 2H), 3.40(dd, J=11.7, 3.0 Hz, 1H), 3.27 (dd, J=11.7, 6.3 Hz, 1H), 2.92 (s, 3H),2.30 (s, 3H), 2.29 (s, 3H).

Example 7(38)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.59(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.46-7.43 (m, 1H), 7.39-7.27 (m, 5H), 7.16 (s, 1H),7.04-6.82 (m, 4H), 6.75-6.67 (m, 3H), 5.14 (s, 2H), 4.74-4.64 (m, 1H),4.31 (dd, J=9.6, 4.5 Hz, 1H), 4.20 (dd, J=9.6, 6.0 Hz, 1H), 3.69 (s,2H), 3.42 (dd, J=11.7, 3.0 Hz, 1H), 3.31 (dd, J=11.7, 6.6 Hz, 1H), 2.93(s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H).

Example 7(39)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.52(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.40-7.23 (m, 5H), 7.20-7.08 (m, 2H), 7.07-6.97 (m, 1H),6.93-6.66 (m, 6H), 5.13 (s, 2H), 4.74-4.64 (m, 1H), 4.30 (dd, J=9.6, 4.5Hz, 1H), 4.20 (dd, J=9.6, 6.6 Hz, 1H), 3.68 (s, 2H), 3.42 (dd, J=11.4,3.0 Hz, 1H), 3.31 (dd, J=11.4, 6.0 Hz, 1H), 2.93 (s, 3H), 2.27 (s, 3H),2.21 (s, 3H), 2.18 (s, 3H).

Example 7(40)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.56(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.39-7.26 (m, 5H), 7.18 (s, 1H), 6.96-6.82 (m, 5H),6.75-6.67 (m, 3H), 5.13 (s, 2H), 4.73-4.63 (m, 1H), 4.30 (dd, J=9.6, 4.5Hz, 1H), 4.20 (dd, J=9.6, 6.3 Hz, 1H), 3.71 (s, 2H), 3.42 (dd, J=11.4,3.0 Hz, 1H), 3.31 (dd, J=11.4, 6.6 Hz, 1H), 2.93 (s, 3H), 2.37 (s, 3H),2.30 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H).

Example 8(1) to Example 8(40)

Using the compound prepared according to example 7(1) to example 7(40)instead of the compound prepared according to example 1, this followinginvention compounds were obtained by the operation similar to example 2.

Example 8(1)4-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)butane

TLC:Rf 0.45(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.72 (d, J=8.7 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.19-7.12(m, 1H), 7.08-6.95 (m, 4H), 6.92-6.80 (m, 2H), 6.76-6.66 (m, 2H),4.73-4.63 (m, 1H), 4.32 (dd, J=9.6, 5.1 Hz, 1H), 4.21 (dd, J=9.6, 6.3Hz, 1H), 3.41 (dd, J=11.7, 2.7 Hz, 1H), 3.28 (dd, J=11.7, 6.6 Hz, 1H),2.92 (s, 3H), 2.78 (t, J=7.5 Hz, 2H), 2.44 (t, J=7.5 Hz, 2H), 2.37 (s,3H), 2.08-1.93 (m, 2H).

Example 8(2)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2,5-dimethylindol-3-yl)aceticacid

TLC:Rf 0.39(methanol:chloroform=1:10);

NMR(CDCl₃):δ 7.71 (d, J=9.6 Hz, 2H), 7.28 (s, 1H), 6.99 (d, J=9.6 Hz,2H), 6.90-6.80 (m, 4H), 6.73-6.70 (m, 2H), 4.67 (m, 1H), 4.30 (dd,J=9.9, 4.8 Hz, 1H), 4.21 (dd, J=9.9, 6.3 Hz, 1H), 3.71 (s, 2H), 3.40(dd, J=11.7, 3.0 Hz, 1H), 3.28 (dd, J=11.7, 6.6 Hz, 1H), 2.92 (s, 3H),2.41 (s, 3H), 2.40 (s, 3H).

Example 8(3)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.42(methanol:chloroform=1:10);

NMR(CDCl₃):δ 7.70 (d, J=9.0 Hz, 2H), 7.15 (m, 1H), 7.00 (d, J=9.0 Hz,2H), 6.95-6.65 (m, 6H), 4.68 (m, 1H), 4.30 (dd, J=9.6, 4.8 Hz, 1H), 4.21(dd, J=9.6, 6.0 Hz, 1H), 3.68 (s, 2H), 3.39 (dd, J=11.7, 2.7 Hz, 1H),3.28 (dd, J=11.7, 6.6 Hz, 1H), 2.91 (s, 3H), 2.39 (s, 3H).

Example 8(4)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-chloro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.40(chloroform:methanol=10:1);

NMR(CDCl₃):δ 7.71 (d, J=9.0 Hz, 2H), 7.47 (d, J=1.8 Hz, 1H), 7.05-6.95(m, 3H), 6.92-6.80 (m, 3H), 6.73-6.70 (m, 2H), 4.69 (m, 1H), 4.31 (dd,J=9.9, 5.1 Hz, 1H), 4.22 (dd, J=9.9, 6.0 Hz, 1H), 3.71 (s, 2H), 3.40(dd, J=11.7, 2.7 Hz, 1H), 3.28 (dd, J=11.7, 6.3 Hz, 1H), 2.92 (s, 3H),2.41 (s, 3H).

Example 8(5)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-trifluoromethyl-2-methylindol-3-yl)aceticacid

TLC:Rf 0.40(chloroform:methanol=10:1);

NMR(CDCl₃):δ 7.78 (s, 1H), 7.71 (d, J=9.0 Hz, 2H), 7.25 (dd, J=8.8, 0.7Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.90-6.80 (m,2H), 6.73-6.65 (m, 2H), 4.67 (m, 1H), 4.31 (dd, J=9.9, 5.1 Hz, 1H), 4.21(dd, J=9.9, 6.0 Hz, 1H), 3.75 (s, 2H), 3.39 (dd, J=11.7, 2.7 Hz, 1H),3.27 (dd, J=11.7, 6.6 Hz, 1H), 2.91 (s, 3H), 2.42 (s, 3H).

Example 8(6)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.52(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=7.8 Hz, 1H), 7.40-7.28 (m, 2H), 7.23-7.13 (m,1H), 7.11-6.95 (m, 2H), 6.94-6.76 (m, 3H), 6.76-6.65 (m, 2H), 4.72-4.62(m, 1H), 4.29 (dd, J=9.9, 5.1 Hz, 1H), 4.19 (dd, J=9.9, 6.3 Hz, 1H),3.72 (s, 2H), 3.40 (dd, J=11.4, 1.8 Hz, 1H), 3.27 (dd, J=11.4, 6.6 Hz,1H), 2.92 (s, 3H), 2.34 (s, 3H), 2.32 (s, 3H).

Example 8(7)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid

TLC:Rf 0.52(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.32 (d, J=8.7 Hz, 1H), 6.96-6.76 (m, 6H), 6.75-6.64 (m,3H), 4.72-4.62 (m, 1H), 4.28 (dd, J=9.6, 5.1 Hz, 1H), 4.18 (dd, J=9.6,6.3 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 2H), 3.40 (dd, J=11.4, 2.7 Hz, 1H),3.27 (dd, J=11.4, 6.6 Hz, 1H), 2.92 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H).

Example 8(8)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.42 (d, J=8.7 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 7.04 (d,J=2.4 Hz, 1H), 7.00-6.80 (m, 4H), 6.75-6.65 (m, 3H), 4.72-4.62 (m, 1H),4.28 (dd, J=9.9, 5.4 Hz, 1H), 4.19 (dd, J=9.9, 6.0 Hz, 1H), 3.83 (s,3H), 3.67 (s, 2H), 3.40 (dd, J=11.7, 3.0 Hz, 1H), 3.27 (dd, J=11.7, 6.6Hz, 1H), 2.92 (s, 3H), 2.82 (s, 3H).

Example 8(9)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.43(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.45 (d, J=2.1 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.02 (dd,J=9.0, 2.1 Hz, 1H), 6.98-6.76 (m, 5H), 6.75-6.67 (m, 2H), 4.72-4.62 (m,1H), 4.28 (dd, J=9.9, 5.4 Hz, 1H), 4.18 (dd, J=9.9, 6.6 Hz, 1H), 3.69(s, 2H), 3.40 (dd, J=11.1, 2.4 Hz, 1H), 3.27 (dd, J=11.1, 6.6 Hz, 1H),2.92 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H).

Example 8(10)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.43(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.31 (d, J=8.7 Hz, 1H), 7.14 (d, J=8.7, 2.4 Hz, 1H), 7.01(dd, J=9.3, 4.5 Hz, 1H), 6.92-6.74 (m, 5H), 6.74-6.66 (m, 2H), 4.72-4.62(m, 1H), 4.29 (dd, J=9.9, 4.8 Hz, 1H), 4.18 (dd, J=9.9, 6.3 Hz, 1H),3.68 (s, 2H), 3.41 (dd, J=11.4, 2.1 Hz, 1H), 3.27 (dd, J=11.4, 6.6 Hz,1H), 2.92 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H).

Example 8(11)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.52-7.42 (m, 2H), 7.33-7.04 (m, 4H), 6.98-6.82 (m, 3H),6.76-6.68 (m, 2H), 4.72-4.64 (m, 1H), 4.29 (dd, J=9.9, 4.8 Hz, 1H), 4.20(dd, J=9.9, 6.0 Hz, 1H), 3.72 (s, 2H), 3.40 (dd, J=12.0, 2.7 Hz, 1H),3.27 (dd, J=12.0, 6.0 Hz, 1H), 2.92 (s, 3H), 2.32 (s, 3H).

Example 8(12)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,3-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.63(chloroform:methanol:acetic acid=9:1:0.1);

NMR(CDCl₃):δ 7.47 (d, J=7.8 Hz, 1H), 7.21-7.16 (m, 2H), 7.06-7.04 (m,2H), 6.91-6.83 (m, 2H), 6.77-6.67 (m, 3H), 4.73-4.66 (m, 1H), 4.30-4.15(m, 2H), 3.71 (s, 2H), 3.45-3.28 (m, 2H), 2.93 (s, 3H), 2.31 (s, 3H),2.24 (s, 6H).

Example 8(13)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.52(chloroform:methanol:acetic acid=9:1:0.1);

NMR(CDCl₃):δ 7.61 (d, J=1.2 Hz, 1H), 7.56 (dd, J=8.7, 2.4 Hz, 1H), 7.50(d, J=7.8 Hz, 1H), 7.16 (dt, J=6.9, 1.2 Hz, 1H), 7.04 (dt, J=8.4, 1.2Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.92-6.82 (m, 3H), 6.73-6.68 (m, 2H),4.74-4.66 (m, 1H), 4.34-4.19 (m, 2H), 3.74 (s, 2H), 3.42 (dd, J=11.4,2.7 Hz, 1H), 3.31 (dd, J=11.4, 6.6 Hz, 1H), 2.92 (s, 3H), 2.41 (s, 3H),2.26 (s, 3H).

Example 8(14)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid

TLC:Rf 0.42(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.32 (d, J=8.4 Hz, 1H), 6.93-6.76 (m, 7H), 6.75-6.66 (m,2H), 4.72-4.62 (m, 1H), 4.28 (dd, J=9.6, 5.1 Hz, 1H), 4.18 (dd, J=9.6,6.6 Hz, 1H), 3.70 (s, 2H), 3.41 (dd, J=11.4, 2.4 Hz, 1H), 3.28 (dd,J=11.4, 6.6 Hz, 1H), 2.92 (s, 3H), 2.40 (s, 3H), 2.34 (s, 3H), 2.30 (s,3H).

Example 8(15)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methoxybenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.65(chloroform:methanol:acetic acid=9:1:0.1);

NMR(CDCl₃):δ 7.50 (d, J=7.5 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.30(dd,J=8.4, 2.1 Hz, 1H), 7.20-7.15(m, 1H), 7.08-6.81 (m, 5H), 6.72-6.66 (m,2H), 4.77-4.69 (m, 1H), 4.38-4.22 (m, 2H), 3.87 (s, 3H), 3.74(s, 2H),3.45-3.26 (m, 2H), 2.91 (s, 3H), 2.42 (s, 3H).

Example 8(16)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-fluorobenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.55(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.57-7.48 (m, 3H), 7.19 (dt, J 7.4, 1.2 Hz, 1H), 7.09-7.03(m, 2H), 6.97 (d, J=8.1 Hz, 1H), 6.92-6.81 (m, 2H), 6.73-6.67 (m, 2H),4.75-4.68 (m, 1H), 4.40-4.25 (m, 2H), 3.74 (s, 2H), 3.45-3.28 (m, 2H),2.92 (s, 3H), 2.42 (s, 3H), 1.90 (brs, 1H).

Example 8(17)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methoxybenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.50(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.50-7.40 (m, 2H), 7.24-7.14 (m, 2H), 7.12-7.04 (m, 1H),6.93-6.83 (m, 2H), 6.76-6.67 (m, 2H), 6.59 (dd, J=8.4, 2.1 Hz, 1H), 6.54(d, J=2.1 Hz, 1H), 4.72-4.64 (m, 1H), 4.30 (dd, J=9.6, 5.1 Hz, 1H), 4.20(dd, J=9.6, 6.0 Hz, 1H), 3.72 (s, 2H), 3.61 (s, 3H), 3.41 (dd, J=11.7,2.7 Hz, 1H), 3.29 (dd, J=11.7, 6.6 Hz, 1H), 2.93 (s, 3H), 2.34 (s, 3H).

Example 8(18)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-chlorobenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.52(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.84 (d, J=2.1 Hz, 1H), 7.62 (dd, J=8.4, 2.1 Hz, 1H), 7.51(d, J=7.8 Hz, 1H), 7.19 (dt, J=6.9, 1.2 Hz, 1H), 7.09-6.96 (m, 3H),6.92-6.82 (m, 2H), 6.73-6.67 (m, 2H), 4.78-4.71 (m, 1H), 4.41-4.24 (m,2H), 3.74 (s, 2H), 3.45 (dd, J=11.4, 2.7 Hz, 1H), 3.36 (dd, J=11.4, 6.0Hz, 1H), 2.93 (s, 3H), 2.42 (s, 3H).

Example 8(19)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.63(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.55 (t, J=8.4 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.20 (dt,J=6.6, 1.5 Hz, 1H), 7.15-7.06 (m, 2H), 6.92-6.83 (m, 3H), 6.75-6.68 (m,3H), 4.72-4.65 (m, 1H), 4.32-4.17 (m, 2H), 3.72 (s, 2H), 3.40 (dd,J=11.4, 2.7 Hz, 1H), 3.27 (dd, J=11.4, 6.3 Hz, 1H), 2.92 (s, 3H), 2.42(s, 3H).

Example 8(20)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid

TLC:Rf 0.45(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.62-7.52 (m, 2H), 7.28 (s, 1H), 6.93-6.81 (m, 5H),6.75-6.66 (m, 2H), 4.74-4.65 (m, 1H), 4.31 (dd, J=9.9, 4.8 Hz, 1H), 4.22(dd, J=9.9, 6.3 Hz, 1H), 3.71 (s, 2H), 3.42 (dd, J=11.7, 3.0 Hz, 1H),3.31 (dd, J=11.7, 6.6 Hz, 1H), 2.92 (s, 3H), 2.41 (s, 3H), 2.40 (s, 3H),2.26 (s, 3H).

Example 8(21)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.48(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.61-7.51 (m, 2H), 7.15 (dd, J 8.7, 2.1 Hz, 1H), 6.98-6.67(m, 7H), 4.74-4.66 (m, 1H), 4.32 (dd, J=9.6, 5.1 Hz, 1H), 4.22 (dd,J=9.6, 6.3 Hz, 1H), 3.69 (s, 2H), 3.42 (dd, J=11.4, 2.4 Hz, 1H), 3.31(dd, J=11.4, 6.6 Hz, 1H), 2.92 (s, 3H), 2.39 (s, 3H), 2.27 (s, 3H).

Example 8(22)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.37(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.60-7.50 (m, 2H), 7.47 (d, J=1.8 Hz, 1H), 6.99 (dd, J=8.7,1.8 Hz, 1H), 6.94-6.81 (m, 4H), 6.75-6.67 (m, 2H), 4.75-4.66 (m, 1H),4.32 (dd, J=9.9, 5.1 Hz, 1H), 4.23 (dd, J=9.9, 6.3 Hz, 1H), 3.70 (s,2H), 3.42 (dd, J=11.7, 3.0 Hz, 1H), 3.31 (dd, J=11.7, 6.6 Hz, 1H), 2.93(s, 3H), 2.40 (s, 3H), 2.27 (s, 3H).

Example 8(23)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid

TLC:Rf 0.40(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.62-7.52 (m, 2H), 6.95 (d, J=2.4 Hz, 1H), 6.93-6.81 (m,4H), 6.76-6.63 (m, 3H), 4.74-4.65 (m, 1H), 4.32 (dd, J=9.6, 5.1 Hz, 1H),4.22 (dd, J=9.6, 6.3 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 2H), 3.42 (dd,J=11.4, 2.7 Hz, 1H), 3.31 (dd, J=11.4, 6.6 Hz, 1H), 2.93 (s, 3H), 2.41(s, 3H), 2.27 (s, 3H).

Example 8(24)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,3-dimethylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.54(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.18-7.02 (m, 3H), 6.92-6.67 (m, 6H), 4.73-4.66 (m, 1H),4.30-4.16 (m, 2H), 3.66 (s, 2H), 3.43 (dd, J=11.4, 2.7 Hz, 1H), 3.32(dd, J=11.4, 6.9 Hz, 1H), 2.93 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 2.23(s, 3H).

Example 8(25)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methoxybenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.58(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.33 (d, J=1.8 Hz, 1H), 7.27 (dd, J=8.7, 1.8 Hz, 1H),7.19-7.14 (m, 1H), 7.00-6.66 (m, 7H), 4.77-4.69 (m, 1H), 4.38-4.22 (m,2H), 3.88 (s, 3H), 3.70 (s, 2H), 3.43 (dd, J=11.4, 2.7 Hz, 1H), 3.30(dd, J=11.4, 6.3 Hz, 1H), 2.91 (s, 3H), 2.40 (s, 3H).

Example 8(26)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-fluorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.43(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.55-7.46 (m, 3H), 7.19-6.70 (m, 7H), 4.75-4.68 (m, 1H),4.40-4.26 (m, 2H), 3.69 (s, 2H), 3.44-3.27 (m, 2H), 2.92 (s, 3H), 2.40(s, 3H).

Example 8(27)2-(1-(3-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.50(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.50 (dd, J=7.8, 0.9 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H),7.34-7.24 (m, 2H), 7.24-7.15 (m, 2H), 7.10-7.02 (m, 2H), 6.91-6.78 (m,2H), 6.74-6.64 (m, 2H), 4.68-4.58 (m, 1H), 4.24 (dd, J=9.9, 5.4 Hz, 1H),4.13 (dd, J=9.9, 6.9 Hz, 1H), 3.73 (s, 2H), 3.36 (dd, J=11.4, 2.7 Hz,1H), 3.23 (dd, J=11.4, 6.3 Hz, 1H), 2.89 (s, 3H), 2.38 (s, 3H).

Example 8(28)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.48(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.44 (d, J=8.7 Hz, 1H), 7.22 (dd, J=8.7, 4.5 Hz, 1H), 7.15(dd, J=8.7, 2.1 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 7.00-6.80 (m, 4H),6.75-6.68 (m, 2H), 4.73-4.63 (m, 1H), 4.29 (dd, J=9.9, 5.4 Hz, 1H), 4.20(dd, J=9.9, 6.0 Hz, 1H), 3.67 (s, 2H), 3.40 (dd, J=11.4, 2.7 Hz, 1H),3.27 (dd, J=11.4, 6.3 Hz, 1H), 2.92 (s, 3H), 2.27 (s, 3H).

Example 8(29)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.48(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.47-7.42 (m, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.10-7.03 (m,2H), 6.99-6.82 (m, 3H), 6.75-6.68 (m, 2H), 4.72-4.62 (m, 1H), 4.29 (dd,J=9.9, 5.1 Hz, 1H), 4.20 (dd, J=9.9, 6.0 Hz, 1H), 3.67 (s, 2H), 3.40(dd, J=11.4, 2.7 Hz, 1H), 3.27 (dd, J=11.4, 6.3 Hz, 1H), 2.92 (s, 3H),2.29 (s, 3H).

Example 8(30)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.40(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.53 (t, J=8.1 Hz, 1H), 7.17-7.12 (m, 2H), 6.92-6.68 (m,7H), 4.75-4.64 (m, 1H), 4.31-4.17 (m, 2H), 3.64 (s, 2H), 3.39 (dd,J=11.4, 3.0 Hz, 1H), 3.26 (dd, J=11.4, 6.3 Hz, 1H), 2.92 (s, 3H), 2.34(s, 3H).

Example 8(31)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.43(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.54 (t, J=8.4 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.11-7.02(m, 2H), 6.92-6.82 (m, 3H), 6.73-6.68 (m, 3H), 4.71-4.65 (m, 1H),4.31-4.17 (m, 2H), 3.67 (s, 2H), 3.39 (dd, J=11.4, 2.7 Hz, 1H), 3.27(dd, J=11.4, 6.3 Hz, 1H), 2.92 (s, 3H), 2.36 (s, 3H).

Example 8(32)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-2,5-dimethylindol-3-yl)aceticacid

TLC:Rf 0.49(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.54 (t, J=8.1 Hz, 1H), 6.99 (d, J=8.1, 1H), 6.92-6.83 (m,4H), 6.74-6.70 (m, 4H), 4.71-4.64 (m, 1H), 4.31-4.17 (m, 2H), 3.71 (s,2H), 3.40 (dd, J=11.7, 2.7 Hz, 1H), 3.27 (dd, J=11.7, 6.3 Hz, 1H), 2.92(s, 3H), 2.42 (s, 6H).

Example 8(33)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid

TLC:Rf 0.42(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.53 (t, J=8.4 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 6.95-6.83(m, 4H), 6.74-6.68 (m, 4H), 4.71-4.64 (m, 1H), 4.31-4.17 (m, 2H), 3.83(s, 3H), 3.68 (s, 2H), 3.40 (dd, J=11.7, 2.7 Hz, 1H), 3.27 (d d, J=11.7,6.6 Hz, 1H), 2.92 (s, 3H), 2.42 (s, 3H).

Example 8(34)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.35(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (t, J=7.5 Hz, 1H), 7.21-7.15 (m, 2H), 7.09-6.99 (m,2H), 6.92-6.82 (m, 2H), 6.75-6.68 (m, 3H), 4.73-4.66 (m, 1H), 4.33-4.18(m, 2H), 3.72 (s, 2H), 3.42 (dd, J=11.4, 2.7 Hz, 1H), 3.31 (dd, J=11.4,6.6 Hz, 1H), 2.93 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H).

Example 8(35)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-2,5-dimethylindol-3-yl)aceticacid

TLC:Rf 0.51(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.43 (d, J=8.7 Hz, 1H), 7.06-6.82 (m, 7H), 6.75-6.67 (m,2H), 4.72-4.62 (m, 1H), 4.29 (dd, J=9.6, 4.8 Hz, 1H), 4.20 (dd, J=9.6,6.3 Hz, 1H), 3.70 (s, 2H), 3.40 (dd, J=11.7, 3.0 Hz, 1H), 3.27 (dd,J=11.7, 6.6 Hz, 1H), 2.92 (s, 3H), 2.41 (s, 3H), 2.32 (s, 3H).

Example 8(36)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.50(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.50 (d, J=7.8 Hz, 1H), 7.42 (s, 2H), 7.22-7.13 (m, 1H),7.09-6.95 (m, 2H), 6.91-6.79 (m, 2H), 6.74-6.65 (m, 2H), 4.73-4.64 (m,1H), 4.12-4.01 (m, 2H), 3.75 (s, 2H), 3.43 (dd, J=11.1, 2.7 Hz, 1H),3.34 (dd, J=11.1, 6.3 Hz, 1H), 2.93 (s, 3H), 2.40 (s, 3H), 2.32 (s, 6H).

Example 8(37)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-trifluoromethoxy-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.37-7.28 (m, 2H), 7.03 (d, J=9.0 Hz, 1H), 6.96-6.75 (m,5H), 6.75-6.66 (m, 2H), 4.72-4.62 (m, 1H), 4.29 (dd, J=9.6, 4.8 Hz, 1H),4.19 (dd, J=9.6, 6.3 Hz, 1H), 3.70 (s, 2H), 3.40 (dd, J=11.4, 2.7 Hz,1H), 3.27 (dd, J=11.4, 6.6 Hz, 1H), 2.92 (s, 3H), 2.33 (s, 3H), 2.32 (s,3H).

Example 8(38)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.44(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.45 (d, J=2.1 Hz, 1H), 7.16 (s, 1H), 7.01 (dd, J=9.0, 2.1Hz, 1H), 6.98-6.82 (m, 3H), 6.76-6.67 (m, 3H), 4.75-4.65 (m, 1H), 4.31(dd, J=9.9, 4.8 Hz, 1H), 4.20 (dd, J=9.9, 6.6 Hz, 1H), 3.69 (s, 2H),3.42 (dd, J=11.7, 2.7 Hz, 1H), 3.31 (dd, J=11.7, 6.6 Hz, 1H), 2.93 (s,3H), 2.32 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H).

Example 8(39)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid

TLC:Rf 0.44(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.19-7.11 (m, 2H), 7.06-6.96 (m, 1H), 6.93-6.67 (m, 6H),4.74-4.64 (m, 1H), 4.31 (dd, J=9.6, 3.9 Hz, 1H), 4.20 (dd, J=9.6, 6.6Hz, 1H), 3.68 (s, 2H), 3.42 (dd, J=11.7, 3.0 Hz, 1H), 3.31 (dd, J=11.7,6.3 Hz, 1H), 2.93 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H).

Example 8(40)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid

TLC:Rf 0.44(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.18 (s, 1H), 6.94-6.82 (m, 5H), 6.76-6.67 (m, 3H),4.74-4.64 (m, 1H), 4.30 (dd, J=9.9, 5.1 Hz, 1H), 4.20 (dd, J=9.9, 6.6Hz, 1H), 3.71 (s, 2H), 3.43 (dd, J=11.7, 3.0 Hz, 1H), 3.31 (dd, J=11.7,6.6 Hz, 1H), 2.93 (s, 3H), 2.40 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H),2.18 (s, 3H).

Example 9(1) to Example 9(15)

Using the compound prepared according to reference example 11, thesubstitute derivatives,(2S)-2-hydroxymethyl-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazine, or thesubstitute derivatives, this following invention compounds were obtainedby the operation similar to example 4.

Example 9(1)2-(1-(4-(quinolin-3-ylmethoxy)benzoyl)-2-methylindol-3-yl)acetic acidallylic ester

TLC:Rf 0.66(hexane:ethyl acetate=2:1);

NMR(CDCl₃):δ 9.01 (d, J=2.4 Hz, 1H), 8.23 (s, 1H), 8.15 (d, J=8.1 Hz,1H), 7.87 (d, J=7.8 Hz, 1H), 7.79-7.74 (m, 3H), 7.63-7.50 (m, 2H),7.19-6.98 (m, 5H), 5.91 (m, 5H), 5.84 (s, 2H), 5.84-5.19 (m, 2H),4.61-4.59 (m, 2H), 3.74 (s, 2H), 2.43 (s, 3H).

Example 9(2)2-(1-(4-(2-phenyloxazol-5-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid allylic ester

TLC:Rf 0.66(hexane:ethyl acetate=4:1).

Example 9(3)2-(1-(4-(1-methylindol-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid allylic ester

TLC:Rf 0.42(hexane:ethyl acetate=3:1).

Example 9(4)2-(1-(4-((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.40(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.8 Hz, 1H), 7.36-7.24 (m, 5H), 7.20-7.00 (m,4H), 6.86 (d, J=2.1 Hz, 1H), 6.78 (dd, J=8.4, 2.1 Hz, 1H), 6.64-6.58 (m,3H), 5.13 (s, 2H), 4.74-4.64 (m, 1H), 4.27 (dd, J=9.9, 5.1 Hz, 1H), 4.17(dd, J=9.9, 6.3 Hz, 1H), 3.74 (s, 2H), 3.36 (dd, J=11.4, 2.7 Hz, 1H),3.22 (dd, J=11.4, 6.6 Hz, 1H), 2.88 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H).

Example 9(5)2-(1-(4-((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.50(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.38-7.35 (m, 5H), 7.21-6.99 (m,4H), 6.86 (d, J=2.4 Hz, 1H), 6.78 (dd, J=8.7, 2.4 Hz, 1H), 6.73-6.60 (m,3H), 5.13 (s, 2H), 4.72-4.62 (m, 1H), 4.27 (dd, J=9.3, 5.4 Hz, 1H), 4.17(dd, J=9.3, 6.3 Hz, 1H), 3.74 (s, 2H), 3.36 (dd, J=11.1, 2.4 Hz, 1H),3.22 (dd, J=11.1, 6.6 Hz, 1H), 2.88 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H),2.23 (s, 3H).

Example 9(6)2-(1-(4-((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.50(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.40-7.24 (m, 5H), 7.22-7.00 (m,4H), 6.86 (d, J=2.4 Hz, 1H), 6.83-6.69 (m, 2H), 6.56-6.44 (m, 2H), 5.13(s, 2H), 4.68-4.58 (m, 1H), 4.27 (dd, J=9.9, 5.1 Hz, 1H), 4.16 (dd,J=9.9, 6.0 Hz, 1H), 3.74 (s, 2H), 3.39 (dd, J=11.7, 2.7 Hz, 1H), 3.25(dd, J=11.7, 6.3 Hz, 1H), 2.91 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 2.28(s, 3H).

Example 9(7)2-(1-(4-((3R)-5-methyl-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.68(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.50-7.44 (m, 1H), 7.38-7.24 (m, 6H), 7.21-6.97 (m, 4H),6.86-6.80 (m, 1H), 6.79-6.70 (m, 2H), 5.13 (s, 2H), 4.71 (t, J=8.7 Hz,1H), 4.53 (dd, J=9.3, 5.1 Hz, 1H), 4.21 (dd, J=9.3, 6.0 Hz, 1H), 4.05(t, J=8.7 Hz, 1H), 3.98-3.86 (m, 1H), 3.74 (s, 2H), 2.31 (s, 6H), 2.29(s, 3H).

Example 9(8)2-(1-(4-((3R)-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.53(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.40-6.72 (m, 15H), 5.13 (s, 2H),4.73 (t, J=9.0 Hz, 1H), 4.55 (dd, J=9.6, 5.1 Hz, 1H), 4.28-3.90 (m, 3H),3.74 (s, 2H), 2.31 (s, 3H), 2.29 (s, 3H).

Example 9(9)2-(1-(4-(2-(3-methylpyridine-6-yl)ethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.60(hexane:ethyl acetate=1:1);

NMR(CDCl₃):δ 8.41-8.38 (m, 1H), 7.50-7.40 (m, 2H), 7.35-7.12 (m, 8H),7.09-6.98 (m, 2H), 6.81 (d, J=2.1 Hz, 1H), 6.77-6.71 (m, 1H), 5.12 (s,2H), 4.41 (t, J=6.6 Hz, 2H), 3.73 (s, 2H), 3.25 (t, J=6.6 Hz, 2H), 2.32(s, 3H), 2.30 (s, 3H), 2.27 (s, 3H).

Example 9(10)2-(1-(4-(5-methyl-1,3-dioxanindan-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.66(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.38-7.24 (m, 6H), 7.22-6.97 (m,3H), 6.90-6.58 (m, 5H), 6.45 (t, J=4.2 Hz, 1H), 5.13 (s, 2H), 4.31 (d,J=4.2 Hz, 2H), 3.73 (s, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H).

Example 9(11)2-(1-(4-((3R)-5-fluoro-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.63(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.36-7.24 (m, 6H), 7.20-7.00 (m,4H), 6.82 (d, J=3.0 Hz, 1H), 6.75 (dd, J=8.7, 3.0 Hz, 1H), 6.68-6.56 (m,2H), 5.13 (s, 2H), 4.80-4.64 (m, 2H), 4.44-4.37 (m, 1H), 4.17-4.02 (m,2H), 3.73 (s, 2H), 2.31 (s, 3H), 2.28 (s, 3H).

Example 9(12)2-(1-(4-((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.58(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.36-7.24 (m, 6H), 7.21-7.12 (m,1H), 7.10-6.99 (m, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.82-6.70 (m, 2H),6.45-6.31 (m, 2H), 5.13 (s, 2H), 4.74-4.64 (m, 1H), 4.27 (dd, J=9.9, 5.7Hz, 1H), 4.16 (dd, J=9.9, 6.3 Hz, 1H), 3.74 (s, 2H), 3.41 (dd, J=11.4,3.0 Hz, 1H), 3.30 (dd, J=11.4, 6.9 Hz, 1H), 2.92 (s, 3H), 2.32 (s, 3H),2.29 (s, 3H).

Example 9(13)2-(1-(4-(1-ethylindolin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.75(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.8 Hz, 1H), 7.36-7.24 (m, 6H), 7.21-7.00 (m,5H), 6.85 (d, J=2.7 Hz, 1H), 6.76 (dd, J=8.4, 2.7 Hz, 1H), 6.66 (t,J=7.8 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.13 (s, 2H), 4.24-4.05 (m, 3H),3.74 (s, 2H), 3.47-3.24 (m, 3H), 2.95-2.85 (m, 1H), 2.32 (s, 3H), 2.30(s, 3H), 1.17 (t, J=6.9 Hz, 3H).

Example 9(14)2-(1-(4-(4-methyl-1,3-dioxanindan-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.53(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.5 Hz, 1H), 7.36-7.25 (m, 6H), 7.20-6.98 (m,3H), 6.90-6.57 (m, 4H), 6.46 (t, J=3.3 Hz, 1H), 5.13 (s, 2H), 4.34 (d,J=3.3 Hz, 2H), 3.74 (s, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H).

Example 9(15)2-(1-(4-((3R)-7-methyl-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester

TLC:Rf 0.60(hexane:ethyl acetate=7:3);

NMR(CDCl₃):δ 7.47 (d, J=7.8 Hz, 1H), 7.36-7.20 (m, 6H), 7.20-6.90(m,5H), 6.86-6.72 (m, 3H), 5.13 (s, 2H), 4.72 (t, J=9.0 Hz, 1H), 4.55 (dd,J=9.0, 5.1 Hz, 1H), 4.25-3.90 (m, 3H), 3.73 (s, 2H), 2.31 (s, 3H), 2.28(s, 3H), 2.24 (s, 3H).

Example 10(1) to Example 10(15)

Using the compound prepared according to example 9(1) to example 9(15)instead of the compound prepared according to example 1, this followinginvention compounds were obtained by the operation similar to example 2.

Example 10(1)2-(1-(4-(quinolin-3-ylmethoxy)benzoyl)-2-methylindol-3-yl)acetic acid

TLC:Rf 0.61 (methanol:chloroform=1:10);

NMR(CDCl₃):δ 9.02 (d, J=0.9 Hz, 1H), 8.47 (s, 1H), 8.07-8.00 (m, 2H),7.78 (m, 1H), 7.70-7.60 (m, 3H), 7.50 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.4Hz, 2H), 7.13 (t, J=7.8 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.95 (d, J=8.1Hz, 1H), 5.47 (s, 2H), 3.68 (s, 2H), 2.28 (s, 3H).

Example 10(2)2-(1-(4-(2-phenyloxazol-5-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.55(chloroform:methanol=10:1);

NMR(CDCl₃):δ 8.06 (m, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.55-7.45 (m, 3H),7.30 (s, 1H), 7.15 (m, 1H), 7.09-6.95 (m, 5H), 5.20 (s, 2H), 3.73 (s,2H), 2.42 (s, 3H).

Example 10(3)2-(1-(4-(1-methylindol-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.46(methanol:chloroform=1:10);

NMR(DMSO-d₆):δ 7.67 (d, J=9.0 Hz, 2H), 7.56-7.45 (m, 3H), 7.27 (d, J=9.0Hz, 2H), 7.30-7.10 (m, 2H), 7.05-7.00 (m, 2H), 6.97 (m, 1H), 6.66 (s,1H), 5.45 (s, 2H), 3.79 (s, 3H), 3.68 (s, 2H), 2.28 (s, 3H).

Example 10(4)2-(1-(4-((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.45(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.52-7.46 (m, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.23-7.15 (m,1H), 7.10-6.97 (m, 2H), 6.90-6.86 (m, 1H), 6.82-6.77 (m, 1H), 6.64-6.57(m, 3H), 4.74-4.64 (m, 1H), 4.27 (dd, J=9.6, 5.1 Hz, 1H), 4.18 (dd,J=9.6, 6.0 Hz, 1H), 3.74 (s, 2H), 3.35 (dd, J=11.1, 3.3 Hz, 1H), 3.22(dd, J=11.1, 6.6 Hz, 1H), 2.88 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H).

Example 10(5)2-(1-(4-((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.45(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.49 (d, J=7.2 Hz, 1H), 7.36-6.97 (m, 4H), 6.88 (d, J=2.4Hz, 1H), 6.79 (dd, J=9.0, 2.4 Hz, 1H), 6.73-6.60 (m, 3H), 4.72-4.62 (m,1H), 4.28 (dd, J=9.6, 5.1 Hz, 1H), 4.18 (dd, J=9.6, 6.3 Hz, 1H), 3.73(s, 2H), 3.36 (dd, J=11.4, 2.7 Hz, 1H), 3.21 (dd, J=11.4, 6.3 Hz, 1H),2.88 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H), 2.23 (s, 3H).

Example 10(6)2-(1-(4-((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.45(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=7.8 Hz, 1H), 7.36-6.96 (m, 4H), 6.90-6.84 (m,1H), 6.83-6.75 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.56-6.45 (m, 2H),4.68-4.58 (m, 1H), 4.27 (dd, J=9.9, 5.4 Hz, 1H), 4.17 (dd, J=9.9, 6.6Hz, 1H), 3.73 (s, 2H), 3.39 (dd, J=12.0, 2.7 Hz, 1H), 3.25 (dd, J=12.0,6.6 Hz, 1H), 2.91 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H).

Example 10(7)2-(1-(4-((3R)-5-methyl-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.49(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=8.1 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.19 (td,J=8.1, 0.9 Hz, 1H), 7.12-6.96 (m, 4H), 6.87-6.80 (m, 1H), 6.79-6.71 (m,2H), 4.70 (t, J=8.7 Hz, 1H), 4.53 (dd, J=9.6, 5.1 Hz, 1H), 4.21 (dd,J=9.6, 5.7 Hz, 1H), 4.05 (t, J=8.7 Hz, 1H), 3.98-3.86 (m, 1H), 3.73 (s,2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H).

Example 10(8)2-(1-(4-((3R)-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.49(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.51-7.45 (m, 1H), 7.35-7.28 (m, 2H), 7.25-6.80 (m, 7H),6.79-6.73 (m, 1H), 4.73 (t, J=8.4 Hz, 1H), 4.55 (dd, J=9.3, 5.1 Hz, 1H),4.21 (dd, J=9.3, 5.7 Hz, 1H), 4.08 (t, J=8.4 Hz, 1H), 4.02-3.90 (m, 1H),3.72 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H).

Example 10(9)2-(1-(4-(2-(3-methylpyridin-6-yl)ethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 8.42 (d, J=1.5 Hz, 1H), 7.58-7.46 (m, 2H), 7.30-7.13 (m,3H), 7.07-6.95 (m, 2H), 6.75 (d, J=2.1 Hz, 1H), 6.61 (dd, J=8.7, 2.1 Hz,1H), 4.29 (t, J=6.3 Hz, 2H), 3.71 (s, 2H), 3.23 (t, J=6.3 Hz, 2H), 2.33(s, 3H), 2.32 (s, 3H), 2.25 (s, 3H).

Example 10(10)2-(1-(4-(5-methyl-1,3-dioxanindan-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=7.5 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.23-7.02(m, 2H), 6.97 (d, J=7.5 Hz, 1H), 6.90-6.85 (m, 1H), 6.83-6.60 (m, 4H),6.44 (t, J=4.2 Hz, 1H), 4.31 (d, J=4.2 Hz, 2H), 3.72 (s, 2H), 2.34 (s,3H), 2.31 (s, 3H), 2.29 (s, 3H).

Example 10(11)2-(1-(4-((3R)-5-fluoro-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.22-6.97(m, 4H), 6.84 (d, J=2.4 Hz, 1H), 6.76 (dd, J=8.4, 2.4 Hz, 1H), 6.67-6.57(m, 2H), 4.80-4.64 (m, 2H), 4.44-4.36 (m, 1H), 4.18-4.03 (m, 2H), 3.72(s, 2H), 2.34 (s, 3H), 2.32 (s, 3H).

Example 10(12)2-(1-(4-((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=7.5 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.18 (td,J=7.5, 0.9 Hz, 1H), 7.10-6.96 (m, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.83-6.70(m, 2H), 6.45-6.30 (m, 2H), 4.65-4.55 (m, 1H), 4.27 (dd, J=9.9, 5.1 Hz,1H), 4.16 (dd, J=9.9, 6.3 Hz, 1H), 3.72 (s, 2H), 3.41 (dd, J=11.4, 2.7Hz, 1H), 3.30 (dd, J=11.4, 6.9 Hz, 1H), 2.91 (s, 3H), 2.34 (s, 3H), 2.32(s, 3H).

Example 10(13)2-(1-(4-(1-ethylindolin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.22-6.97(m, 5H), 6.86 (d, J=2.1 Hz, 1H), 6.77 (dd, J=8.7, 2.1 Hz, 1H), 6.66 (t,J=7.8 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 4.30-4.04 (m, 3H), 3.72 (s, 2H),3.47-3.22 (m, 3H), 2.89 (dd, J=16.2, 7.2 Hz, 1H), 2.34 (s, 3H), 2.33 (s,3H), 1.17 (t, J=7.5 Hz, 3H).

Example 10(14)2-(1-(4-(4-methyl-1,3-dioxanindan-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=7.5 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.19 (t,J=7.5 Hz, 1H), 7.10-6.95 (m, 2H), 6.92-6.87 (m, 1H), 6.84-6.66 (m, 4H),6.45 (t, J=3.9 Hz, 1H), 4.34 (d, J=3.9 Hz, 2H), 3.73 (s, 2H), 2.35 (s,3H), 2.32 (s, 3H), 2.24 (s, 3H).

Example 10(15)2-(1-(4-((3R)-7-methyl-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid

TLC:Rf 0.53(chloroform:methanol=9:1);

NMR(CDCl₃):δ 7.48 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.23-7.10(m, 2H), 7.10-6.90 (m, 3H), 6.88-6.73 (m, 3H), 4.72 (t, J=8.7 Hz, 1H),4.59-7.51 (m, 1H), 4.25-4.16 (m, 1H), 4.15-3.90 (m, 2H), 3.72 (s, 2H),2.34 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H).

Formulation Example 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 5 mg of active ingredient.2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1, 4-benzoxazine- 5.0 g2-ylmethoxy)benzoyl)-2-methylindol-3-yl)acetic acid Carboxymethylcellulose calcium(disintegrator) 0.2 g Magnesium stearate(lubricant) 0.1g Microcrystalline cellulose 4.7 g

Formulation Example 2

After the following components were admixed in conventional method, thesolution was sterilized in conventional manner, placed 5 ml portionsinto ampoules and freeze-dried to obtain 100 ampoules each containing 20mg of the active ingredient. 2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2- 2.0 g ylmethoxy)benzoyl)-2-methylindol-3-yl)acetic acidMannitol 20 g Distilled water 1000 mL

1. An indole derivative compound represented by formula (I):

wherein R¹ represents (1) —COR⁶ or (2) —CH₂OR⁷, R⁶ represents (1) ahydroxyl group, (2) C1-6 alkoxy group, (3) —NR⁸R⁹, (4) C1-6 alkoxy groupsubstituted by phenyl group, or (5) C2-6 alkenyloxy group, R⁷ represents(1) a hydrogen atom or (2) C2-6 acyl group, R⁸ and R⁹ represent (1)hydrogen atom, (2) C1-6 alkyl group or (3) —SO₂R¹⁰, respectively, R¹⁰represents (1) C1-6 alkyl group, (2) carbocyclic ring 1 (3) orheterocycle 1, D represents (1) a single bond, (2) C1-6 alkylene group,(3) C2-6 alkenylene group, or (4) —O—(C1-6 alkylene)- group, R²represents (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) halogenatom, (4) trihalomethyl group, (5) cyano group, or (6) hydroxyl group,R³ and R⁴ represent (1) a hydrogen atom, (2) C1-6 alkyl group, and (3)C1-6 alkoxy group, (4) C1-6 alkyl group substituted in by C1-6 alkoxygroup, (5) a halogen atom, (6) nitro group, (7) —NR¹¹R¹², (8)trihalomethyl group, (9) cyano group, (10) hydroxyl group, or (11)trihalomethoxy groups, respectively, R¹¹ and R¹² represent a hydrogenatom or C1-6 alkyl group, respectively, m represents 1 to 4, nrepresents 1 to 4, R⁵ represents (1)

(2) C1-6 alkyl group substituted by C1-6 alkoxy group, or (3) C1-6alkoxy group substituted by C1-6 alkoxy group, G represents (1) a singlebond, (2) C1-6 alkylene groupI (alkylene group may be substituted byhydroxyl group or C1-4 alkoxy group) that may be replaced by 1 or 2oxygen atom(s) and/or sulfur atom(s), (3) C2-6 alkenylene group(alkenylene group may be substituted by hydroxyl or C1-4 alkoxy group)that may be replaced by 1 or 2 oxygen atom(s) and sulfur atom(s), (4)—CONR¹³—, (5) —NR¹⁴CO—, (6) —SO₂NR¹⁵—, (7) —NR¹⁶SO₂—, or (8) —N═N—, R¹³,R¹⁴, R¹⁵, and R¹⁶ represent a hydrogen atom or C1-6 alkyl group,respectively,

represents (1) carbocyclic ring 2 or (2) heterocycle 2, respectively,carbocyclic ring 1 and carbocyclic ring 2 represent C3-15 monocycle,dicyclic or tricycle carbocyclic ring aryls that may be saturated all orpartially, respectively, heterocycle 1 and heterocycle 2 represent C3-15monocycle, dicyclic, or tricycle heterocyclic ring aryls that may besaturated all or partially, which contained 1 to 5 of hetero atom(s)selected from oxygen atom, nitrogen atom, and sulfur atom, respectively,carbocyclic ring 1, carbocyclic ring 2, heterocycle 1, and heterocycle 2may be substituted by 1-5 group(s) selected from (1) C1-6 alkyl group,(2) C1-10 alkoxy group, (3) C1-6 alkyl group substituted by C1-6 alkoxygroup, (4) halogen atom, (5) hydroxyl group, (6) trihalomethyl group,(7) nitro group, (8) —NR¹⁷R¹⁸, (9) phenyl group, (10) phenoxy group,(11) oxo group, (12) C2-6 acyl group, (13) cyano group, and (14)—SO₂R¹⁹, respectively, R¹⁷ and R¹⁸ represent hydrogen atom or C1-6 alkylgroup, respectively, R¹⁹ represents C1-6 alkyl group, and

represents (1) a single bond or (2) a double bond, except for2-(1-(4-benzyloxybenzoyl)-2-methyl-5-methoxyindol-3-yl) acetic acidmethyl or a non-toxic salt thereof.
 2. The indole derivative compound ofclaim 1, wherein R¹ is —COR⁶, or a non-toxic salt thereof.
 3. The indolederivative compound of claim 1, wherein R¹ is —CH₂OR⁷, or a non-toxicsalt thereof.
 4. The indole derivative compound of claim 2, wherein thecompound is (1)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (2)2-(1-(4-((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (3)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (4)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (5)3-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)propanoicacid, (6)2-(1-(4-propoxymethylbenzoyl)-2-methyl-5-methoxyindol-3-yl)acetic acid,(7) 2-(1-(4-(2-ethoxyethyl)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (8) 2-(1-(4-phenoxybenzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (9) 2-(1-(4-benzyloxybenzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (10)2-(1-(4-(2-phenylethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (11)2-(1-(4-(2-methoxyethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (12)2-(1-(4-(2-ethoxyethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (13)2-(1-(3-(2-phenylethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (14)2-(1-(3-(2-ethoxyethoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (15)2-(1-(4-(3-phenylpropoxy)benzoyl)-2-methyl-5-methoxyindol-3-yl)aceticacid, (16)2-(1-(4-((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (17)2-(1-(4-((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (18)2-(1-(4-((3R)-5-fluoro-2,3-dihydrobenzofuran-3-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (19)2-(1-(4-(2,3-dihydrobenzofuran-3-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (20)2-(1-(4-(2-(6-methylpyridin-2-yl)ethoxy)benzoyl)-2-methylindol-3-yl)acetate,(21)2-(1-(4-(2-(3-methylpyridin-2-yl)ethoxy)benzoyl)-2-methylindol-3-yl)acetate,(22)2-(1-(4-((2R)-1,4-benzodioxan-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)acetate,(23)2-(1-(4-(1,3-dioxanindan-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (24)2-(1-(4-((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (25)2-(1-(4-((2S)-2,3-dihydrobenzofuran-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (26)2-(1-(4-((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, or a non-toxic salt thereof.
 5. The indole derivative compound ofclaim 2, wherein the compound is (1)(2E)-4-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)-2-butenoicacid benzyl ester, (2)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester, (3)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (4)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester, (5)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-trifluoromethyl-2-methylindol-3-yl)aceticacid benzyl ester, (6)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (7)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid benzyl ester, (8)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid benzyl ester, (9)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester, (10)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (11)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (12)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,3-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (13)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (14)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester, (15)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methoxybenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (16)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-fluorobenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (17)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methoxybenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (18)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-chlorobenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (19)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (20)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester, (21)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (22)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester, (23)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid benzyl ester, (24)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,3-dimethylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (25)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methoxybenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (26)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-fluorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (27)2-(1-(3-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (28)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (29)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester, (30)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (31)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester, (32)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester, (33)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid benzyl ester, (34)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (35)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester, (36)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (37)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-trifluoromethoxy-2-methylindol-3-yl)aceticacid benzyl ester, (38)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid benzyl ester, (39)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid benzyl ester, (40)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid benzyl ester, (41)2-(1-(4-(quinolin-3-ylmethoxy)benzoyl)-2-methylindol-3-yl)acetic acidallylic ester, (42)2-(1-(4-(2-phenyloxazol-5-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid allylic ester, (43)2-(1-(4-(1-methylindol-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid allylic ester, (44)2-(1-(4-((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (45)2-(1-(4-((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (46)2-(1-(4-((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (47)2-(1-(4-((3R)-5-methyl-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (48)2-(1-(4-((3R)-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (49)2-(1-(4-(2-(3-methylpyridine-6-yl)ethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (50)2-(1-(4-(5-methyl-1,3-dioxanindan-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (51)2-(1-(4-((3R)-5-fluoro-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (52)2-(1-(4-((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (53)2-(1-(4-(1-ethylindolin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (54)2-(1-(4-(4-methyl-1,3-dioxanindan-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (55)2-(1-(4-((3R)-7-methyl-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid benzyl ester, (56)4-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)butanoicacid, (57)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2,5-dimethylindol-3-yl)aceticacid, (58)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (59)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-chloro-2-methylindol-3-yl)aceticacid, (60)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-5-trifluoromethyl-2-methylindol-3-yl)aceticacid, (61)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (62)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid, (63)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid, (64)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid, (65)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (66)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-2-methylindol-3-yl)aceticacid, (67)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,3-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid, (68)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (69)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid, (70)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methoxybenzoyl)-2-methylindol-3-yl)aceticacid, (71)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-fluorobenzoyl)-2-methylindol-3-yl)aceticacid, (72)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methoxybenzoyl)-2-methylindol-3-yl)aceticacid, (73)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-chlorobenzoyl)-2-methylindol-3-yl)aceticacid, (74)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-2-methylindol-3-yl)aceticacid, (75)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid, (76)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (77)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid, (78)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methylbenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid, (79)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,3-dimethylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (80)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-methoxybenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (81)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-fluorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (82)2-(1-(3-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (83)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (84)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-chlorobenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid, (85)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (86)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid, (87)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-2,5-dimethylindol-3-yl)aceticacid, (88)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-fluorobenzoyl)-5-methoxy-2-methylindol-3-yl)aceticacid, (89)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid, (90)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid, (91)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3,5-dimethylbenzoyl)-2-methylindol-3-yl)aceticacid, (92)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-5-trifluoromethoxy-2-methylindol-3-yl)aceticacid, (93)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-5-chloro-2-methylindol-3-yl)aceticacid, (94)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-5-fluoro-2-methylindol-3-yl)aceticacid, (95)2-(1-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2,5-dimethylbenzoyl)-2,5-dimethylindol-3-yl)aceticacid, (96)2-(1-(4-(quinolin-3-ylmethoxy)benzoyl)-2-methylindol-3-yl)acetic acid,(97)2-(1-(4-(2-phenyloxazol-5-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (98)2-(1-(4-(1-methylindol-2-ylmethoxy)benzoyl)-2-methylindol-3-yl)aceticacid, (99)2-(1-(4-((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (100)2-(1-(4-((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (101)2-(1-(4-((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (102)2-(1-(4-((3R)-5-methyl-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (103)2-(1-(4-((3R)-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (104)2-(1-(4-(2-(3-methylpyridin-6-yl)ethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (105)2-(1-(4-(5-methyl-1,3-dioxanindan-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (106)2-(1-(4-((3R)-5-fluoro-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (107)2-(1-(4-((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (108)2-(1-(4-(1-ethylindolin-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (109)2-(1-(4-(4-methyl-1,3-dioxanindan-2-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, (110)2-(1-(4-((3R)-7-methyl-2,3-dihydrobenzofuran-3-ylmethoxy)-2-methylbenzoyl)-2-methylindol-3-yl)aceticacid, or a non-toxic salt thereof.
 6. A medicinal composition comprisingthe indole derivative compound represented by formula (I) of claim 1 ora non-toxic salt thereof, and a pharmaceutically acceptable carrier ordiluent.
 7. A method of antagonizing a PGD₂ receptor, said methodcomprising administering to a subject an effective amount of the indolederivative compound represented by formula (I) of claim 1 or a non-toxicsalt thereof.
 8. The method of claim 7, wherein the PGD₂ receptor is aDP receptor.
 9. A method for medical treatment and/or prevention ofallergic diseases, systemic mastocytosis, disorders due to systemicmastocyte activation, anaphylactic shock, bronchoconstriction,urticaria, eczema, allergic bronchopulmonary aspergillosis, paranasalsinusitis, migraine, nasal polyp, hypersensitive angitis, eosinophilia,contact dermatitis, diseases accompanied with itching, secondarydiseases generated by behaviors caused by itching, inflammation, chronicobstructive pulmonary disease, ischemic reperfusion disorder,cerebrovascular disorder, pleuritis complicated by rheumatoid arthritis,or ulcerative colitis, which comprises administering to a subject anindole derivative compound represented by formula (I) of claim 1 or anon-toxic salt thereof.
 10. The method according to claim 9, wherein theallergic disease is selected from the group consisting of allergicrhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthmaand food allergy.
 11. The method according to claim 9, wherein thedisease accompanied with itching is selected from the group consistingof atopic dermatitis, urticaria, allergic conjunctivitis, allergicrhinitis and contact dermatitis.
 12. The method according to claim 9,wherein the secondary disease generated by behaviors caused by itchingis selected from the group consisting of cataracta, retinodialysis,inflammation, infection and dysgryphia.
 13. The method according toclaim 9, wherein the behavior caused by itching is selected fromscratching behaviors and beating.